Wong2016 PDF

PRIMER
Diabetic retinopathy
Tien Y. Wong1,2, Chui Ming Gemmy Cheung1,2, Michael Larsen3, Sanjay Sharma4
and Rafael Simó5
Abstract | Diabetic retinopathy (DR) is a common complication of diabetes mellitus and is a major
cause of vision loss in middle-aged and elderly people. One-third of people with diabetes have DR.
Severe stages of DR include proliferative DR, caused by the abnormal growth of new retinal blood
vessels, and diabetic macular oedema, in which there is exudation and oedema in the central part of
the retina. DR is strongly associated with a prolonged duration of diabetes, hyperglycaemia and
hypertension. It is traditionally regarded as a microvascular disease, but retinal neurodegeneration is
also involved. Complex interrelated pathophysiological mechanisms triggered by hyperglycaemia
underlie the development of DR. These mechanisms include genetic and epigenetic factors, increased
production of free radicals, advanced glycosylation end products, inflammatory factors and vascular
endothelial growth factor (VEGF). Optimal control of blood glucose and blood pressure in individuals
with diabetes remains the cornerstone for preventing the development and arresting the progression
of DR. Anti-VEGF therapy is currently indicated for diabetic macular oedema associated with vision
loss, whereas laser photocoagulation prevents severe vision loss in eyes with proliferative DR.
These measures, together with increasing public awareness and access to regular screening for
DR with retinal photography, and the development of new treatments to address early disease stages,
will lead to better outcomes and prevent blindness for patients with DR.
Diabetes mellitus is a global epidemic with profound A pooled meta-analysis11 of 35 population-based (mostly
morbidity 1. Diabetes leads to a range of complications from developed countries) studies reported that more
grouped into macrovascular (large blood vessel) compli- than 90 million individuals are estimated to have DR, with
cations, such as cardiovascular disease and stroke, and 21 million having DME and 17 million proliferative DR.
microvascular (small blood vessel) complications, such There has been considerable progress in understand-
as kidney disease. Diabetic retinopathy (DR) is a specific ing the key pathogenetic factors involved in the develop
microvascular complication of diabetes and is the lead- ment of DR. Although DR is traditionally regarded as a
ing cause of vision loss in the general population in many microvascular disease, growing evidence supports the
countries, including the adult working population and idea that retinal neurodegeneration is an early event in
the elderly 2–5. Patients with severe degrees of DR have the pathogenesis of DR. For example, a reduction in the
impaired quality of life, reduced physical, emotional and oscillatory potential in electroretinogram tests is the first
social well-being, and use many health-care resources6. m easurable change in retinal function in patients
Without treatment, DR progresses from mild, with diabetes12.
non-proliferative DR to moderate and severe non- Past epidemiological studies and clinical trials have
proliferative DR before the occurrence of proliferative shown that the development risk and progression of
DR, in which there is growth of abnormal new retinal DR can be reduced by controlling blood glucose levels
blood vessels. Concurrently, at any stage of retinopathy, and blood pressure2,13. Landmark clinical trials in the
Correspondence to T.Y.W.
Singapore Eye Research
with exudation and oedema at the macula (the central 1980s and 1990s have also demonstrated that timely
Institute, Singapore National focal point of the retina), patients may also develop laser photocoagulation can prevent moderate to severe
Eye Centre, 11 Third Hospital diabetic macular oedema (DME) (FIG. 1; TABLE 1). vision loss in patients with DME or proliferative DR2,13–15.
Avenue, Singapore 168751, Although DR is present in approximately 30% of In the 2000s, the introduction of intraocular adminis-
Singapore.
individuals with diabetes, only 5–10% may have the tration of anti-vascular endothelial growth factor (anti-
[email protected]
sight-threatening stages of proliferative DR and DME7,8. VEGF) agents and fast, non-invasive imaging in the
Article number: 16012 However, the individual lifetime risk of DR is 50–60% in form of optical coherence tomography (OCT) further
doi:10.1038/nrdp.2016.12
Published online 17 March 2016; a person with type 2 diabetes mellitus (T2DM) and up to revolutionized the management of DME, resulting in
corrected online 7 April 2016 90% in those with type 1 diabetes mellitus (T1DM)9,10. the possibility of reversing vision loss2,3,15,16. Anti-VEGF
NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 1

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PRIMER
Author addresses Epidemiology

Prevalence and incidence of DR
1
Singapore Eye Research Institute, Singapore National DR occurs in people with either T1DM or T2DM.
Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Classical epidemiological studies in the field of ophthal-
Singapore.
mology, such as the Wisconsin Epidemiologic Study
2
Duke–NUS Medical School, National University of
of Diabetic Retinopathy (WESDR), provided detailed
Singapore, Singapore.
3
Department of Clinical Medicine, University of long-term longitudinal data on the prevalence of DR,
Copenhagen, Copenhagen, Denmark. DME and proliferative DR in populations with T1DM or
4
Departments of Ophthalmology and Epidemiology, T2DM9,10,23,24. The WESDR reported that ~75% of people
Queen’s University, Kingston, Ontario, Canada. with diabetes developed DR 10 years after diagnosis, and
5
Vall d’Hebron Research Institute and CIBERDEM (ISCIII), for those with DR at baseline, approximately two-thirds
Barcelona, Spain. developed more severe stages of DR; 20% developed
proliferative DR or DME25. Incidence data from other
therapy for DME has been shown to improve quality of cohorts in people with diabetes in the United Kingdom,
life17 and reduce vision impairment 18; such therapy is Australia and Asia26–31 have become recently available,
also cost-effective19. New clinical trials now suggest that and these studies included white people8,32–34 as well as
anti-VEGF therapy may also be useful for proliferative other racial and ethnic groups (for example, African
DR20. Finally, from a public health perspective, studies American and Hispanic people)7,35. Similarly, prevalence
have shown that regular widespread screening of per- estimates of between 20% and 50% have been reported
sons with diabetes by digital retinal photography enables in other countries, notably in Europe36,37 and Asia38–42.
the identification of patients with mild DR to facilitate Recent epidemiological studies have shown a r ising
early intervention21,22. prevalence of DME over time. Consequently, DME
In this Primer, we discuss trends in the epidemiol- has overtaken proliferative DR as the most common
ogy and risk factors of DR, the underlying pathophysio cause of vision impairment in T2DM. In the recent US
logical mechanisms, the classification and diagnosis, the National Health and Nutrition Examination Survey,
treatment options (including screening), and the impact DME was twice as common as proliferative DR among
of DR on quality of life. people with diabetes8. This trend may be related to the
Non-proliferative diabetic retinopathy Pre-proliferative retinopathy

Microaneurysms form in the blood vessels of the Changes are increasingly severe and
eye, which can burst to leak blood widespread, and include bleeding into the retina
Fovea
centralis Macula lutea
Pupil Macula
Optic nerve
Optic disc
Central vein
of the retina
Retina Central artery
Light Sclera of the retina
Choroid
Hard
exudates
Cornea Lens Retina

Oedema
Scar tissue
Haemorrhage
Diabetic macular oedema Proliferative retinopathy

Vascular leakage and accumulation of plasma New blood vessels and scar tissue form on
constituents in the macula the retina, causing loss of vision
Figure 1 | Clinical stages and main pathogenetic events of diabetic retinopathy. The first pathological
Nature stagePrimers
Reviews | Disease that
can be identified in a fundoscopic examination is non-proliferative diabetic retinopathy (DR), which can be divided into
mild, moderate or severe non-proliferative DR. Diabetic macular oedema can be considered a particular subtype of
non-proliferative DR in which vascular leakage involves the macula. Pre-proliferative or severe non-proliferative DR is
characterized by capillary closures and non-perfused areas. The typical fundoscopic finding is the presence of
‘cotton wool’ spots and intraretinal microvascular abnormalities. Proliferative DR, in which hypoxia has an essential role,
is the final stage of DR and its hallmark is the development of neovascularization. Haemovitreous (that is, bleeding
in the vitreous cavity) and retinal detachment are advanced complications of proliferative DR.
2 | 2016 | VOLUME 2 www.nature.com/nrdp

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PRIMER
Table 1 | Classification of diabetic retinopathy and diabetic macular oedema triglyceride) and DR has not been consistently docu-
mented in studies52,53. However, increasing evidence
Condition Clinical findings*
supports the idea that non-traditional lipid measures
Diabetic retinopathy (DR) (for example, apolipoproteins A and B) are stronger
No DR No abnormalities risk markers of DR than total cholesterol and tri-
Mild non- Microaneurysms only glyceride levels54,55. Other systemic risk factors for
proliferative DR DR include diabetic nephropathy 56, obesity 57, anae-
mia 58, and markers of systemic inflammation and
Moderate non- Any of the following: microaneurysms, retinal dot and blot
proliferative DR haemorrhages, hard exudates or cotton wool spots; no signs of endothelial dysfunction55,59.
severe non-proliferative DR Ocular risk factors for DR include previous cataract
Severe non- Any of the following: intraretinal haemorrhages (≥20 in each of surgery, which is associated with the progression of DR
proliferative DR 4 quadrants), definite venous beading (in 2 quadrants) or intraretinal and the development of DME60,61, and a myopic refract
microvascular abnormalities (in 1 quadrant); no signs of proliferative DR ive error (that is, near sightedness), which appears to
Proliferative DR One or more of the following: neovascularization, vitreous or protect against DR62,63.
preretinal haemorrhages In terms of genetic factors, heritability estimates of
Diabetic macular oedema (DME) 25–50% have been reported in patients with T1DM
who have proliferative DR64,65; however, candidate and
No DME No apparent retinal thickening or hard exudates in the posterior pole
genome-wide association studies have discovered few
Mild DME Some retinal thickening or hard exudates in the posterior pole but new genetic markers for DR in T2DM66,67. Epigenetic
outside the central subfield of the macula (diameter 1,000 microns) mechanisms (that is, DNA methylation, histone modifi
Moderate DME Retinal thickening or hard exudates within the central subfield of the cations of chromatin and non-coding RNAs) have been
macula, but not involving the centre of the macula suggested to play a part in the pathogenesis of DR68,69.
Severe DME Retinal thickening or hard exudates involving the centre of the macula This hypothesis is supported by observations in clinical
Based on data from REF. 106. *Findings are based on dilated ophthalmoscopy for DR and on trials of a lower risk for DR related to the persistence of
dilated binocular, stereoscopic ophthalmoscopy for DME. beneficial effects (‘metabolic memory’) in patients with
T1DM or T2DM who had previously received sustained
declining prevalence of proliferative DR, which is due intensive glycaemic treatment 70,71.
to the improved systemic management of diabetes.
Concurrently, the incidence of DR‑related vision loss has Mechanisms/pathophysiology
declined over the past three decades, most prominently Pathogenesis of DR
in the United States43–45. Again, these observations reflect Extensive research has provided insight into the molecu
a combination of improved systemic management of lar pathways of DR2,15. Metabolic pathways triggered by
diabetes, enhanced public awareness and access to hyperglycaemia in diabetes, such as the polyol and the
screening 44. Nevertheless, in the context of an expanding hexosamine pathways, the de novo synthesis of diacyl
diabetes epidemic worldwide, particularly in developing glycerol72 by protein kinase C, and the production of
countries where awareness, systemic control and access free radicals and advanced glycosylation end prod-
to general health-care and eye-care services are more ucts (AGEs), seem to be central to the development of
limited, the magnitude of DR-associated blindness will DR73. In addition, accumulating evidence indicates that
remain substantial. neurodegeneration, neuroinflammation and renin–
angiotensin system (RAS) activation also have impor-
Risk factors for DR tant roles in DR development 74–76. Furthermore, the
The most consistent risk factors for the development of aberrant production of mitochondria-derived reactive
DR are long duration of diabetes, hyperglycaemia and oxygen species and endoplasmic reticulum (ER) stress
hypertension9,10,23,46 (BOX 1). However, there is substantial are also involved in the pathogenesis of DR. The roles of
variation in the onset and severity of DR that cannot mitochondrial impairment and oxidative stress in the
be fully explained by hyperglycaemia and hypertension. development of DR have been reviewed extensively77. ER
Indeed, studies have shown that a proportion of patients stress results from an impairment of the folding capacity
with poor glycaemic and/or blood pressure control do of the ER, causing an accumulation of unfolded proteins
not develop DR47, whereas others with appropriate con- in the ER lumen and activation of the unfolded protein
trol develop severe stages of DR48, suggesting that other response. ER stress contributes to increased oxidative
risk factors have a role. stress as well as inflammation and apoptosis, owing to
Puberty and pregnancy are also well-known risk fac- the failure of the unfolded protein response to resolve
tors for DR, particularly in T1DM49,50. The risk of DR ER stress. This condition is likely to be involved in the
related to pregnancy may be mediated by fluctuating pathogenesis of different neuronal diseases in the brain
glucose levels, but other systemic factors (for example, and retina, including the early stages of DR78.
hypertension and pre-eclampsia, and hyperdynamic
circulatory state) are also involved49. Development and progression
Although there are strong pathophysiological The chronopathology of DR is slow and can be separ
reasons to suggest that dyslipidaemia is a risk factor 51, ated into four overlapping clinical stages: retinal
the relationship between dyslipidaemia, measured using damage without any visible microvascular abnormal-
traditional lipid measures (that is, total cholesterol and ities in a fundoscopic examination; non-proliferative

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PRIMER
Box 1 | Risk factors for diabetic retinopathy excitatory neurotransmitter and its enhancement in
the extracellular space results in neuron death (excito
Common and established risk factors toxicity)84. The retina synthesizes neuroprotective fac-
• Hyperglycaemia: a 1% reduction in glycated haemoglobin (HbA1c) serum levels is tors such as pigment epithelium-derived factor (PEDF),
associated with an approximately 35% reduction in risk of diabetic retinopathy (DR) somatostatin, interstitial retinol-binding protein and
development, 15–25% reduction in DR progression, 25% reduction in several neurotrophins74. These neuroprotective factors
vision-threatening DR and 15% reduction in blindness13,128,129,192. are downregulated in the diabetic retina, which might
• Hypertension: a 10 mm Hg reduction in systolic blood pressure is associated with compromise the neuroprotection against the neurotoxic
an approximately 40–50% reduction in DR progression, need for laser treatment factors involved in neurodegeneration.
and vision loss13,134.
However, not all neuroprotective factors are down-
• Diabetes duration: a duration of diabetes of ≥20 years is associated with DR regulated in the diabetic retina. For example, VEGF and
development in 50–90% of patients9,10.
erythropoietin are two well-recognized neuroprotective
• Cataract surgery: cataract surgery is associated with an increased risk of DR factors that are upregulated74. VEGF is upregulated in
progression and diabetic macular oedema development60,61.
the very early stages of the neurodegenerative process.
• Life stages: pregnancy193–195 and puberty49,195 are associated with an increased risk The accumulation of glutamate85 and the loss of PEDF86
of DR progression.
and somatostatin87 are mechanisms involved in VEGF
• Nephropathy: diabetic nephropathy is closely correlated with DR56. overexpression. This finding is important because
Less-common or less-established risk factors the increase in VEGF levels as a consequence of the
• Dyslipidaemia: biologically plausible but inconsistent associations between neurodegenerative process links neurodegeneration
dyslipidaemia and DR have been reported in different studies. Some studies suggest with early microvascular impairment (that is, blood–
DR risk is associated with increased triglyceride levels, whereas diabetic macular retinal barrier breakdown). Other factors linking
oedema risk is associated with increased low-density lipoprotein and decreased neurodegeneration and early microvascular impair-
high-density lipoprotein levels51–53. ment are inflammation, upregulation of receptors for
• Obesity: an increased waist/hip ratio and body mass index is associated with DR risk57. AGEs (RAGE) and RAS activation74. Both erythro-
• Anaemia: a strong but uncommon association between anaemia and DR risk has poietin and its receptor are synthesized by the human
been reported58. retina (mainly in the retinal pigment epithelium) 88.
• Inflammatory markers: inconsistent associations have been reported59. Erythropoietin is a powerful neuroprotective factor,
• Ethnicity: Hispanic and South Asian populations show inconsistent associations7,8,11,32. and very high levels of this hormone are found in the
• Genetic factors: few genetic risk markers have been identified67. vitreous fluid of patients with diabetes89. Erythropoietin
is also an important stimulus for the mobilization of
endothelial progenitor cells towards injured retinal sites;
retinal microvascular changes (mild and moderate non- thus, erythropoietin is also involved in the remodelling
proliferative DR with or without DME); more advanced of damaged tissue90. VEGF and erythropoietin over-
pre-proliferative changes (severe non-proliferative expression occur in parallel with the downregulation
DR); and proliferative DR and advanced stages of DR of neuroprotective factors and, therefore, may partly
(FIG. 1). The main pathogenetic events involved in the counteract any reduction of the neuroprotective fac-
development of DR are highlighted in FIG. 2. tors mentioned above. However, in advanced stages
of DR the high levels of VEGF and/or erythropoietin
Retinal damage without visible microvascular abnor- could favour neovascularization and so contribute to
malities. Hyperglycaemia and associated metabolic proliferative DR90,91. In addition, erythropoietin could
pathways can lead to neurodegeneration, early micro- potentiate the effects of VEGF. Thus, overexpression of
vascular impairment and neurovascular unit impair- VEGF and erythropoietin is a double-edged sword in
ment (FIG. 3). Neurovascular unit impairment includes the pathogenesis of DR.
the alteration of neurovascular coupling, a physiological Finally, the increased intraretinal production of
process whereby neural activity is coupled to blood endothelin 1 that occurs in the diabetic retina can
flow and metabolism. This coupling permits the retina induce retinal neurodegeneration, contributing to the
to regulate blood flow in response to neural activity crosstalk between endothelial cells and the neuroretina.
or metabolic demands79. The two hallmarks of retinal Accordingly, the early impairment of endothelial cells
neurodegeneration are neural apoptosis and reactive could contribute to neurodegeneration through the
gliosis. These features were confirmed in histopatho- activation of endothelin receptors92,93.
logical examinations of eyes of organ donors with dia-
betes who did not show clinical DR in ophthalmological Mild and moderate non-proliferative DR and DME. The
examinations 1–2 years before death80,81. The loss of neu- first vascular changes in the retina that are observed on
ral cells results in the thinning of the retinal ganglion cell histopathology are thickening of the basement mem-
layer and nerve fibre layer, which can now be detected brane, an endothelial injury that leads to the disrup-
by spectral domain OCT82,83. tion of the tight junctions and pericyte loss15 (FIG. 2).
Extracellular glutamate accumulation and an imbal- The consequences of pericyte loss are vascular tone
ance in the retinal production of neuroprotective fac- dysregulation and the growth and proliferation of
tors are two of the most important pathogenetic factors endothelial cells owing to the deficit of transforming
involved in diabetes-induced retinal neurodegener growth factor‑β produced by pericytes. These changes
ation 74 (BOX 2; FIG. 3) . Glutamate is the principal underlie the development of microaneurysms and dot

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PRIMER
intraretinal haemorrhages, two of the earliest detectable blood–retinal barrier breakdown. Ageing and hyper
clinical abnormalities seen in early non-proliferative tension, two frequent conditions associated with T2DM,
DR. The thickening of the basement membrane and the also increase the expression of pro-inflammatory mol
disruption of the tight junctions are determining fac- ecules in the retina94,95. Increased levels of inflammatory
tors in the leakage of the retinal capillaries. Although mediators may lead to an early and persistent chronic
thickened, the basement membrane is dysfunctional and inflammatory condition in the diabetic retina that results
permits the passage of the intravascular content (pro- in leukocyte activation, leukocyte adhesion to the vas-
teins, lipids, inflammatory mediators and other plasma cular endothelium (leukostasis) and alteration of the
constituents) to the interstitial space. VEGF and pro-in- blood–retina barrier, which then leads to increased
flammatory cytokines (IL‑1β, tumour necrosis factor, vascular permeability 96,97. The clinical consequence of
IL‑6, IL‑8 and monocyte chemoattractant protein 1) this process is the occurrence of hard exudates, which
produced by glial cells (Müller cells and microglia), the represent the leakage of plasma constituents and mainly
retinal pigment epithelium and macrophages also have consist of lipids and proteins. DME is a consequence of
essential roles in early microvascular impairment and this leakage in the macula region.
The main pathogenetic factors of DME are also
RPE
VEGF and pro-inflammatory cytokines. As men-
tioned above, the main source of pro-inflammatory
VEGF Macrophage cytokines is local synthesis by the retina. Circulating
Photoreceptor cytokines that are increased in T2DM could also
layer
Pro-inflammatory
increase the vascular leakage, but their contribution
OLM cytokines to DME development remains uncertain. Although
Cone Rod
ONL hypoxia is the most well-characterized factor that
induces VEGF gene expression, chronic hyper
OPL Horizontal glycaemia, AGEs98 and pro-inflammatory cytokines
cell
(for example, IL‑1β and IL‑6) could upregulate VEGF
mRNA expression99. This finding explains why VEGF is
Bipolar
INL cell
overexpressed in DME despite the absence of overt
hypoxia. Blood–retina barrier disruption and vascular
Amacrine cell Müller
glial cell leakage in the macular region leads to DME p rogression
from mild to severe forms (TABLE 1).
IPL Severe non-proliferative DR. In later stages of non-

proliferative DR (that is, severe non-proliferative DR
Dot haemorrhage or pre-proliferative DR), severe endothelial damage
Ganglion cell
GCL occurs and the balance of vasoactive factors synthesized
Hard exudates by the endothelium leans towards the vasoconstrictor
NFL
agents (for example, endothelin and thromboxane A2).
ILM Pericyte Microaneurysm
In addition, nitric oxide is quenched by AGEs, which
Basement are upregulated in the retina of individuals with dia-
membrane
Tight junction Vasoconstrictor betes. Thus, there is a clear predominance of vaso
constriction, favouring a hypoxic environment. As
Basement Tight Pericyte loss the disease progresses, endothelial cell loss becomes
membrane junction New blood
thickening failure
a generalized phenomenon, and the capillaries con-
vessel formation
sist of tubes of thickened basement membrane, which
Healthy Non-proliferative Pre-proliferative Proliferative are highly thrombogenic, and could become occluded
DR DR DR
either by platelet-fibrin aggregation or leukocytes. These
Figure 2 | Main pathogenetic events in diabetic retinopathy. Schematic representation two pathways — vasoconstriction and capillary occlu-
Nature Reviews | Disease Primers sion — are crucial in worsening the ischaemia and the
of the main pathogenetic events in the development and progression of diabetic
retinopathy (DR) depicted from healthy (left) to advanced-stage DR (right). consequence is pre-proliferative DR. In addition, angio
Non-proliferative DR is characterized by vascular changes such as thickening of the poietin 1 receptor (TIE2) is a major regulator of vascular
basement membrane, endothelial injury that leads to the disruption of the tight junctions integrity and is involved in pathological angiogenesis100.
and pericyte loss, resulting in dot haemorrhages, microaneurysms and hard exudates. The main clinical finding in a fundoscopic examin
Vascular endothelial growth factor (VEGF) and pro-inflammatory cytokine production ation of an eye with severe non-proliferative DR is
(IL‑1β, tumour necrosis factor, IL‑6, IL‑8 and monocyte chemoattractant protein 1) by the the presence of ‘cotton wool’ spots. These lesions are
retinal pigment epithelium (RPE), glial cells and macrophages also contribute to the manifestations of stasis in the axoplasmic flow, which,
vascular changes. Endothelial damage leads to vasoconstriction owing to vasoconstrictor
in the setting of DR, indicate areas of retinal ischaemia
release (endothelin 1 and thromboxane A2) and hypoxia in pre-proliferative DR, which is
aggravated owing to the capillary occlusion. The severe hypoxia in end-stage DR leads to or infarction. Dilated capillaries and shunts between
neovascularization. These new blood vessels tend to grow into the vitreous body and are arteries and veins can also be identified and are referred
prone to rupture. GCL, ganglion cell layer; ILM, inner limiting membrane; INL, inner to as intraretinal microvascular abnormalities. In addi-
nuclear layer; IPL, inner plexiform layer; NFL, nerve fibre layer; OLM, outer limiting tion, retinal veins appear dilated, tortuous and irregular
membrane; ONL, outer nuclear layer; OPL, outer plexiform layer. in calibre.

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PRIMER
Proliferative DR. The end stage in the natural history or fundoscopic examination is a broad term cover-
of DR is proliferative DR and its subsequent complica- ing three types of tests: direct fundoscopy, indirect
tions. The main pathogenetic factor involved is a severe fundos copy and slit lamp microscopy. Other causes
hypoxia, which leads to an imbalance between angio- of retinopathy should be excluded3,15,16, as these micro-
genic (for example, VEGF) and anti-angiogenic (for vascular lesions are not specific to diabetes and milder
example, PEDF) mediators that favours neovascular levels of retinopathy are common in the general popu
ization, the hallmark of proliferative DR. The first step lation and may be related to hypertension, anaemia
for neovascularization is the proteolytic digestion of the and other factors102–104. In fact, T2DM is defined by
basement membrane, in which the proteases released by the glycaemic level (fasting level of 7.0 mg per dl)
leukocytes have an essential role. The proteolytic frag- at which the prevalence of retinopathy signs begin
ments of the basement membrane and the angiogenic to rise sharply above the normal population level of
factors stimulated by hypoxia, especially VEGF, lead to approximately 10%105.
the migration and replication of endothelial cells, and Clinically, DR is classified as mild, moderate and
finally new vessels appear. These new vessels are fragile severe non-proliferative DR and proliferative DR
owing to architectural weakness, are prone to bleed- (TABLE 1), with proliferative DR further classified based
ing and tend to grow into the vitreous body in which on the location of the new vessels, either on the optic
they are eventually anchored by means of fibrovascular disc or elsewhere 72. Mild, non-proliferative DR is
tissue. This fibrotic tissue may contract and this can defined by capillary microaneurysms and a few intra-
lead to advanced DR and tractional retinal detachment, retinal dot and blot haemorrhages (FIG. 4a,b). These
accompanied by severe vision loss101. Retinal detach- lesions can become evident years after the onset of
ment and vitreous haemorrhage constitute the advanced T1DM but are often seen at the time of diagnosis in
stage of DR and are sight-threatening conditions. T2DM106. As disease progresses to moderate and severe
non-proliferative DR stages, lesion density increases.
Diagnosis, screening and prevention Disease progression is also associated with other signs
Diagnosis reflecting capillary leakage, seen as oedema and intra-
By definition, DR is restricted to people with dia retinal hard exudates, or signs reflecting capillary
betes and is defined as a spectrum of retinal micro occlusion associated with ischaemic damage of the
vascular lesions seen on retinal examination. A retinal nerve fibre layer, seen as cotton wool spots (FIG. 4b),
venous dilation and beading, and intraretinal micro-
vascular abnormalities. Neovascularization in the ret-
Metabolic pathways induced by hyperglycaemia ina signals the onset of proliferative DR (FIG. 4c), with
a risk of vitreous haemorrhage and traction retinal
detachment, and anterior segment neovascularization
Neurovascular
unit impairment of the iris (rubeosis) or anterior chamber angle with
Early microvascular impairment: Neurodegeneration
intraocular pressure rise (neovascular glaucoma)3. The
• Abnormal haemodynamic
response risk of progression to proliferative DR is proportional
ET1 and ET
• BRB breakdown receptors to severity; 5% of mild non-proliferative DR progress
• Glutamate accumulation
(excitotoxicity) to proliferative DR within 1 year, compared with
• Imbalance in the retinal 20% of moderate and 50% of severe non-proliferative
production of neuroprotective DR. DME is separately classified as mild, moder
factors
ate and severe (FIG. 4d), and may occur even in mild,
• VEGF and other vasoactive agents non-proliferative DR72.
• Inflammatory mediators ↓SMS, CORT, NTFs, Fluorescein angiography — a test in which retinal
• RAGE upregulation • Neuron death PEDF and RBP photographs are taken after systemic injection of a
• RAS activation • Glial cell dysfunction ↑VEGF and EPO vegetable-based, fluorescent dye — has traditionally
been used to locate the sources and extent of vascular
Figure 3 | Potential mechanisms linking neurodegeneration and microangiopathy
Nature Reviews | Disease Primers
in diabetic retinopathy. The metabolic pathways induced by hyperglycaemia lead to leakage, the presence of ischaemia, and in planning
neurodegeneration, early microvascular impairment and neurovascular unit impairment. laser photocoagulation therapy. However, there is now
The accumulation of glutamate in the extracellular space (that is, the intersynaptic cleft no longer a strong rationale for using standard fluo-
of retinal neurons) and the decrease in the retinal production of neuroprotective factors rescein angiography routinely, although studies using
are key events for neuron apoptosis and glial dysfunction. However, this process also wide-field fluorescein angiography are underway and
induces the overexpression of vascular endothelial growth factor (VEGF)196, which has a may change the utility of angiography 106,107.
key role in the disruption of the blood–retinal barrier (BRB). Apart from VEGF and other OCT is a newer non-contact technology that creates
vasoactive agents, there are other factors that link neurodegeneration and early high-resolution cross-sectional images of the retina to
microvascular impairment, such as the upregulation of inflammatory mediators and document 3D structural changes, such as thickening of
receptors for advanced glycosylation end products (RAGE) and activation of the renin–
different retinal layers owing to oedema, which cannot
angiotensin system (RAS). In addition, an increase in the intraretinal production of
endothelin 1 (ET1) can induce retinal neurodegeneration, thus contributing to the be readily assessed via clinical fundoscopic examin
crosstalk between endothelial cells and the neuroretina. CORT, cortistatin; EPO, ation of retinal photography (FIG. 5). OCT has been
erythropoietin; NMDA, N‑methyl-d‑aspartate; NTFs, neurotrophins; PEDF, pigment particularly useful for monitoring DME progression
epithelium-derived factor; RBP, inter-photoreceptor retinoid-binding protein; over the course of intravitreal injection therapies for
SMS, somatostatin. DME (see Management below).

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PRIMER
Box 2 | Links between neurodegeneration and microvascular impairment adults114. Nevertheless, there remains a lack of consensus
on the best mode of screening. Although detailed clin
The main molecular links between neurodegeneration and microvascular impairment ical examination by an ophthalmologist using a slit-lamp
in diabetic retinopathy (DR) are as follows: microscopy instrument remains ideal, logistical chal-
• Endothelin 1: endothelin is synthesized by endothelial cells and is a potent lenges are considerable, and it is impossible for ophthal-
vasoconstrictor that exerts its action through type A and type B endothelin receptors. mologists to screen every person with diabetes, as this
Endothelin 1 exerts neuroprotective actions on top of its vasoactive role and therefore is a highly inefficient use of resources even if adequate
has an essential role in neurovascular coupling.
trained ophthalmologists are available.
• Glutamate: glutamate is the principal excitatory neurotransmitter, and increased levels The major technical innovation in the past two
of glutamate in the extracellular space induces retinal neuron death (excitotoxicity).
decades has been the introduction of digital retinal
The N‑methyl-d‑aspartate (NMDA) receptor is a glutamate receptor.
photography without the need for pharmacological pupil
• Somatostatin: in the eye, somatostatin is a peptide that is mainly synthesized by retinal
dilation (non-mydriatic retinal photography)110,111,115,
pigment epithelial cells and has neuroprotective and anti-inflammatory actions.
and the expansion and adoption of telemedicine to
• Cortistatin: cortistatin is very similar to somatostatin, shares its receptors,
transmit digital images between locations22,116. These
has neuroprotective actions in the retina and is synthesized in the retinal
pigment epithelium.
technologies have the potential to offer fast, systematic
large-scale solutions to DR screening to both developed
• Pigment epithelium-derived factor: this protein is a powerful anti-angiogenic factor
and developing countries. For example, nurses or tech-
with neuroprotective properties.
nicians can take a retinal photograph at the commu-
• Retinol-binding protein: interstitial or retinol-binding protein is crucial for the visual
nity or primary care setting (image capture sites), and
cycle (physiological and biochemical changes associated with perception of a light
stimulus at the retina) and is an essential carrier of nutrients for photoreceptors. transmit the retinal images via the Internet to a central
location where trained technicians can evaluate the
• Neurotrophins: neurotrophic factors (NTFs) are a family of structurally and functionally
related proteins that are essential for the growth, differentiation and survival of several photographs for signs and stages of DR (retinal grading
cell types, including retinal neurons, glial cells and endothelial cells. The main members centre). Results are then transmitted back to the image
of this family are nerve growth factor and brain-derived neurotrophic factor. capture sites, either directly to primary care physicians
• Vascular endothelial growth factor: vascular endothelial growth factor (VEGF) is or ophthalmologists. A meta-analysis demonstrated
required for normal vascular development, is also a survival factor essential for the that non-mydriatic retinal photographs taken by non-
integrity of endothelial cells and exerts neuroprotective actions. VEGF medical technicians is associated with an 80% sensitivity
overexpression in DR leads to hyperpermeability (vascular leakage) and induces for detecting DR, well above the 60% recommended for
proliferation of capillaries in advanced-stage DR, resulting in neovascularization cost-effectiveness117. Telemedicine, national-level DR
(the hallmark of proliferative DR). screening programmes with quality assurance, is widely
• Erythropoietin: erythropoietin is abundantly synthesized by the retinal pigment practiced in the United Kingdom118. The threshold for
epithelium and has potent neurotrophic action in the retina. In addition, erythropoietin referral to subsequent examinations by an ophthal
stimulates the mobilization of endothelial progenitor cells towards injured retinal sites. mologist can be set at varying levels of DR severity
However, when VEGF is overexpressed, erythropoietin could enhance its angiogenic according to international criteria or local guidelines
properties, contributing to the progression to proliferative DR.
and preferences118,119. The UK systemic screening pro-
grammes in particular have provided the foundation for
innovative models exploring the feasibility, safety and
In addition to these assessments, there are multiple cost-effectiveness of extending screening beyond the
early functional and structural abnormalities of the yearly screening 120,121.
retina that can be identified before definitive signs of Irrespective of screening methods, assessment of
microangiopathy have developed2. Such abnormalities patients’ best-corrected visual acuity and systemic
include subnormal electroretinographic oscillatory diabetes profile may allow determination of overall
potentials, downregulation of endothelial junction pro- compliance and general risks, and thereby influence
teins, and upregulation of markers of glial activity and the urgency of referral109. Furthermore, retinal photo
inflammation. However, the clinical utility of assessing graphy screening only captures DR and does not screen
these early functional changes is unclear 108. for other eye conditions such as cataract or glaucoma,
which are also common in individuals with diabetes.
Screening There are three emerging advances in DR screening.
DR meets all of the criteria for screening: it is highly First, DME screening using retinal photography relies
prevalent, it is largely confined to a well-defined popu on an indirect assessment based on the detection of
lation (people with diabetes), it is easy to detect and it hard exudates near the fovea122 (FIG. 4d). As indicated,
is asymptomatic until advanced. Moreover, screening clinical fundoscopic examination or retinal photography
methods are non-invasive and well accepted, and there cannot objectively assess the thickness of the retina seen
are clear treatment modalities for early-stage disease. in DME that can be measured by OCT. Thus, an inte-
DR screening coupled with timely, pre-symptomatic grated screening programme combining photography
intervention is a rational and cost-effective strategy for screening for all people with diabetes, with selected use
the prevention of blindness109–111. Results from studies of OCT in cases in which DME is suspected122, may
have suggested that systematic, national screening pro- reduce false-positive cases (presumed DME based on
grammes for DR can reduce blindness from diabetes by photographic signs but no retinal thickening on OCT).
30–50%112–114, and this would translate to a reduction of However, the logistics and costs of having OCT in a DR
more than 10% of all cases of blindness in working-age screening programme are challenging. Second, newer

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PRIMER
HbA1c (for example, from 9% to 8%) lowers the risk

a b
Haemorrhage of retinopathy by 30–40%128. In addition, the benefit of
early intensive glycaemic control can be long-lasting
Microaneurysm (metabolic memory). This effect was demonstrated by
or haemorrhage a 72–87% risk reduction in progression of DR that was
even seen 4 years after completion of the DCCT study,
when patients in the intensive treatment group had
HbA1C levels return to levels >7%130.
Microaneurysm The effect of intensive glycaemic control in T2DM
or haemorrhage was also investigated in the UKPDS129. Patients were
Cotton wool spots
randomly assigned to either intensive treatment with
c d sulfonylurea and/or insulin, or conventional treatment
with diet control for an average of 10 years. The inten-
Hard exudates Blot sive glucose control group maintained a lower HbA1c
haemorrhage level (of ~7.0%) than the conventional treatment
group (HbA1c level of 7.9%). Over 12 years, intensive
glucose control resulted in 21% reduction in risk for
DR129. Importantly, a long-term beneficial effect (meta
New blood vessel
bolic memory) was evident, with the protective effect
formation at the Microaneurysm Hard exudates of initial intensive therapy observable 25 years after
optic disc or haemorrhage randomization (24% relative risk reduction for micro-
vascular disease)131. However, the additional benefit of
Figure 4 | Clinical signs of diabetic retinopathy on fundoscopic examination.
Nature Reviews | Disease Primers achieving even lower HbA1c levels (towards normo
a | Mild non-proliferative diabetic retinopathy (DR) with microaneurysms and glycaemia) with intensive glycaemic therapy is less clear.
haemorrhage. b | Moderate non-proliferative DR with microaneurysms, haemorrhage The Action to Control Cardiovascular Risk in Diabetes
and cotton wool spots. c | Proliferative DR showing new blood vessels at the optic disc.
(ACCORD) 132 eye study was a subgroup of 2,856
d | Diabetic macular oedema showing hard exudates at the fovea centre.
patients within the main ACCORD study, designed to
evaluate the effects of intensive glycaemic control, inten-
photographic techniques are being tested, including sive blood pressure control and lipid management on
wide-field fundus photography, whereby larger areas of the progression of DR in patients with T2DM selected
the retina can be captured in a single image than tradi- for increased cardiovascular risk. Intensive glycaemic
tional cameras that can image only a limited part of the therapy (target HbA1c levels of 6.0% versus 7.0–7.9%)
retina123,124. Third, new automated DR detection software significantly reduced the risk of progression of DR at
to aid photographic assessment has been developed125,126. 4 years (7.3% versus 10.4% with standard therapy)132.
Although the cost-effectiveness of these technologies However, the Action in Diabetes and Vascular Disease:
has not been thoroughly tested, their use will probably Preterax and Diamicron MR Controlled Evaluation133
increase in the future. trial did not show an additional benefit of more inten-
sive glucose control compared with intensive control
Prevention (HbA1c levels of 6.5% versus 7.5%) for reduction of
Glycaemic control. In addition to screening, DR can new or worsening retinopathy over 5 years133, although
be prevented by the effective systemic control of a further 21% reduction of risk for nephropathy was
glycaemia and blood pressure in patients with dia reported in the more intensive glucose control group
betes3,15,16,127. The Diabetes Control and Complications compared with the intensive control group. The
Trial (DCCT)71,128 and the United Kingdom Prospective ADVANCE133 trial randomly assigned 11,140 patients
Diabetes Study (UKPDS)129 have provided strong evi- with T2DM and an additional risk factor for a vascu-
dence that a tighter control of glycaemia (target gly- lar event into four categories using a factorial design
cated haemoglobin (HbA1c) level of <7%) reduces the of intensive lowering of glucose (target HbA1c level of
risk of development and progression of DR in both 6.5%) versus standard glucose therapy (target HbA1c
T1DM and T2DM. Although a small risk of initial level of 7.0%), and additional routine blood pressure
worsening of retinopathy at the onset of therapy exists, lowering versus routine blood pressure lowering. The
the long-term benefits outweigh this risk128. Over a ADVANCE trial did not show any beneficial effect of
7‑year period, the DCCT reported that intensive ther- either therapy on DR. Furthermore, any potential bene
apy to maintain HbA1c levels of ~7% (compared with fit on DR should also be balanced against the increased
~9% in those with T1DM) reduced the onset of new risk of having a hypoglycaemic event in the intensive
DR by 76% in the primary intervention cohort (which glycaemic therapy group, as the intensive therapy group
recruited patients with no DR at baseline). Moreover, had an increased rate of death from any cause in the
progression of existing DR in the secondary inter- ACCORD study 133.
vention cohort (which recruited patients with pre-
existing mild DR) was reduced by 50%128. Therefore, it Blood pressure control. In terms of controlling blood
is important to achieve glycaemic control early, prefer pressure in patients with diabetes who also have hyper-
ably before the onset of DR. Each per cent reduction in tension, to prevent DR, the clinical evidence is also

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PRIMER
robust. In the UKPDS, tighter blood pressure control the control versus treated group, and its short (2‑year)
(target blood pressure of <150/85 mm Hg versus a less follow‑up. The Diabetic Retinopathy Candesartan Trials
tight control target of <180/105 mm Hg) reduced the (DIRECT) programme examined effects of candesar
risks of DR progression and need for laser treatment tan (an angiotensin receptor blocker) in T1DM 136
by approximately one-third and vision loss by 50% and T2DM 136,137. In T1DM, 5 years of c andesartan
in T2DM129. However, in contrast to glycaemic con- treatment resulted in a reduction in the incidence of
trol, these benefits are not sustainable (no ‘memory’) DR compared to placebo (hazard ratio of 0.82), but
without ongoing and long-term maintenance of blood no beneficial effect on DR progression in those with
pressure control134. pre-existing DR was observed136. In T2DM with mild
Certain blood pressure-lowering medications, par- to moderate DR, 5 years of candesartan treatment
ticularly those targeting the RAS, can exert beneficial resulted in DR regression by 34%137. An overall change
actions other than lowering the blood pressure level. towards less severe DR was observed in the candesartan
The EURODIAB controlled trial of lisinopril (an group in T2DM. The Renin Angiotensin System Study
angiotensin-converting enzyme inhibitor) in insulin- (RASS) evaluated the effect of enalapril (an angiotensin
dependent diabetes (EUCLID) study investigated the converting enzyme inhibitor) and losartan (an angio-
effect of lisinopril on retinopathy in non-hypertensive tensin receptor blocker) on DR progression in T1DM138.
patients with T1DM who were normoalbuminuric or After 5 years, the risk of DR progression was reduced
microalbuminuric. One hundred and seventeen patients by 65% with enalapril and 70% with losartan, indepen
were randomly assigned to the placebo group and dent of blood pressure. These trials suggest that specific
103 patients were randomized to the lisinopril group. drugs that target the RAS may be superior to stand-
The results showed that lisinopril reduced the risk of ard blood pressure-lowering medications in reducing
DR and proliferative DR progression by 50% and 80%, retinopathy risk.
respectively 135. However, the EUCLID study had limi-
tations in terms of differences in baseline glycaemia in Lipid control. Although dyslipidaemia has also been
linked to risk of DR, the effects of statin therapy on DR
risk have been inconsistent 51. The strongest evidence
a from two independent randomized trials suggests that
Cystoid
spaces Nerve fenofibrate could reduce the risk of vision-threatening
Inner limiting membrane Inner nuclear layer fibre layer DR in T2DM. The Fenofibrate Intervention and Event
Inner plexiform layer Lowering in Diabetes study assessed the effects of
Outer plexiform layer fenofibrate on cardiovascular outcomes in patients
with T2DM who did not take statins139. Laser treatment
Retina pigment epithelium
for DR, a pre-specified tertiary outcome, was reduced
Choroid by 37% in the fenofibrate group compared to a pla-
Outer nuclear layer
cebo group after 5 years. The number needed to treat
b Cystoid with fenofibrate to prevent laser treatment was only
spaces 17 in people with existing DR at study entry 139. In a
sub-study, progression of DR after 4.7 years was signifi
cantly lower in the fenofibrate group compared to a
placebo group in patients with DR at baseline (14.6%
versus 3.1%)139. The ACCORD eye trial, in addition to
investigating the effect of intensive glycaemic control,
also evaluated the effect of adding fenofibrate to stat-
c ins to evaluate the effect of this combination on DR132.
Intraretinal
cysts After 4 years, the fenofibrate group had reduced pro-
gression of DR compared to standard treatment (6.5%
versus 10.2%)132. In terms of the mechanisms of action,
fenofibrate has been suggested to also influence non-
lipid mechanisms (for example, VEGF levels)140, but
specific mechanisms remain to be fully elucidated.
Management
Figure 5 | Optical coherence tomography showing treatment outcomes
Nature Reviews for Primers
| Disease Vision loss as a consequence of severe DR can be mini
diabetic macular oedema. Optical coherence tomography (OCT) images of a mized by intervention using intraocular anti-VEGF
patient with type 2 diabetes with diabetic macular oedema (DME). a | OCT image of
agents for DME, panretinal laser photocoagulation
a patient with vision of 6/45 (vision of 6/6 is considered normal vision and 6/60 is
considered legal blindness in some countries) showing fluid accumulation in cystoid
for proliferative DR, and vitrectomy for vitreous
spaces before intravitreal injections of ranibizumab (an anti-vascular endothelial growth haemorrhage and traction retinal detachment 3,14–16,109.
factor therapy) were started. b | Vision of 6/18 (that is, vision improved from 6/45 to 6/18) Intravitreal anti-VEGF therapy has also been shown to
was observed after three intravitreal injections of ranibizumab. c | Vision of 6/9 (that is, reduce the level of DR141, and its potential utility for treat-
vision improved from 6/18 to 6/9, almost normal vision) was observed after seven ment of proliferative DR has now been demonstrated in
intravitreal injections of ranibizumab. recent clinical trials20.

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PRIMER
Laser photocoagulation injections are usually performed in office settings

For almost three decades, laser photocoagulation has by ophthalmologists using an aseptic technique and
been the standard ocular treatment for proliferative DR topical anaesthesia.
and DME14,15. The mechanism of action of laser photo- The activation of inflammatory pathways has been
coagulation is not fully understood, but one hypothesis proposed as one of the mechanisms in DME patho-
is that laser photocoagulation-induced scars alleviate genesis. Corticosteroids suppress multiple pathways of
hypoxia and affects the haemodynamics of the retinal inflammation and have been advocated as a treatment
circulation. Improved retinal oxygenation reduces neo- option for DME, particularly in cases refractory to laser
vascularization and oedema formation by reducing the photocoagulation. In addition, corticosteroids down-
production of VEGF and other factors, and by trigger regulate VEGF expression144 and reduce the induction
ing haemodynamic changes14. The primary goal for of VEGF by pro-inflammatory mediators. However, the
most patients receiving laser therapy is to preserve use- introduction of anti-VEGF agents confined the use of
ful vision and prevent blindness, and reversal of vision corticosteroids to selected patients, such as those with
loss is uncommon. previous cataract surgery and with chronic DME.
Two landmark trials provided the evidence for the Off-label use of triamcinolone (a long-acting
use of laser photocoagulation for DR. The Diabetic corticosteroid) has been shown to reduce DME and to
Retinopathy Study (DRS) demonstrated that pan improve vision in the short-term145. The DR Clinical
retinal laser photocoagulation reduced the risk of Research Network (DRCRnet) reported that the bene-
severe vision loss from 33.0% to 13.9% at 5 years fits of intravitreal triamcinolone did not persist beyond
in patients with proliferative DR or severe non- 1 year, and by 2 years the visual outcome was generally
proliferative DR 142. The Early Treatment Diabetic not better than laser photocoagulation146. Importantly,
Retinopathy Study (ETDRS) demonstrated that focal considerable adverse effects (such as cataract and
laser photocoagulation reduced the risk of vision loss glaucoma) are common. In addition, there are con-
in patients with clinically significant DME from 24% cerns of increased risk of infectious endophthalmitis
to 12%, but did not eliminate this risk142,143. However, (an eye infection) owing to the immunosuppressive
only 3% of patients had a significant improvement in properties of corticosteroid and also sterile (non-
visual acuity, which is partly explained by the ceiling infectious) endophthalmitis, which may be precipi-
effect caused by the relatively good baseline vision tated by additives in the t riamcinolone preparation or
in the study population. Furthermore, laser photo bacterial endotoxins147.
coagulation itself is associated with significant ocular Two sustained-release intravitreal implants have
side effects due to its inherent destructive nature to the recently been evaluated for DME. Ozurdex (Allergan,
retina, including induction of scotoma (that is, a blind Irvine, California, USA) is a biodegradable implant
spot), enlargement of laser scars and development of that is inserted using a 22‑gauge applicator and
secondary neovascularization. releases 0.7 mg of dexamethasone over 120–180 days.
In one trial, significantly more patients in the Ozurdex
Intraocular steroids group achieved ≥15 letter improvement (improve-
In the 2000s, intraocular administration of steroids and ment in ~3 lines on the standard Snellen visual acuity
anti-VEGF agents were introduced as new treatment chart) in best corrected visual acuity compared with
modalities for DME and proliferative DR. Intraocular the sham group (22.2% versus 12%, P < 0.018) over
Table 2 | Randomized controlled trials of anti-VEGF therapy for diabetic macular oedema
Trial name Number of Anti-VEGF agent Vision results (%)* Follow‑up Refs
eyes (months)
Gained Lost
RISE and RIDE 377 Ranibizumab 34–46 (12–18) 2–4 (9–10) 24 153
DR Clinical Research 854 Ranibizumab (+ laser) 28–30 (15) 2 (8) 24 146
Network Protocol I
READ‑2 126 Ranibizumab (± laser) 23 (17) 3% (6) 24 156
RESOLVE 151 Ranibizumab (± laser) 32 (10) 3 (20) 12 155
RESTORE 345 Ranibizumab (± laser) 23 (8) 1–3 (8) 12 154
BOLT 80 Bevacizumab 32 (4) 0 (14) 24 145
DA VINCI 176 Aflibercept 46 (11) NR 12 157
VIVID and VISTA 872 Aflibercept 31–41 (7.8–9.1) 0–0.7 (9–10) 12 158
DR Clinical Research 102 Aflibercept 68 1 12 159
Network Protocol T
102 Bevacizumab 42 2 12
101 Ranibizumab 50 2 12
Based on data from REF. 196. NR, not reported; VEGF, vascular endothelial growth factor. *Percentage of patients with ≥3‑line
vision gain or loss (versus laser photocoagulation therapy alone).

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PRIMER
Diabetic macular oedema visual acuity compared with ranibizumab and bevaci-
zumab. Another comparative effectiveness randomized
clinical trial conducted by the DRCRnet evaluated the
Assessment effectiveness at ≤5 years of two different regimens of
intravitreal ranibizumab combined with focal laser for
DME. Most eyes maintained vision gains obtained dur-
Mild to moderate Moderate to severe
ing treatment for the first year with little need for addi-
No centre involvement Centre involvement tional treatment after 3 years (median 13–17 injections
over 5 years)146,160. Laser photocoagulation performed
immediately at the start of intravitreal ranibizumab
Visual acuity Visual acuity treatment is not superior to delaying laser treatment
better than 20/30 20/30 or worse
for ≥4 weeks, and half of eyes in the group treated with
Treatment intravitreal ranibizumab may avoid laser for ≥5 years
failure with this approach. These results suggest that in con-
Focal or grid laser photocoagulation Anti-VEGF therapy
trast to treatment for neovascular wet (advanced-stage)
Clinical OCT age-related macular degeneration, anti-VEGF treatment
for DME appears to allow the tapering of injection
Figure 6 | Management of diabetic macular oedema.Nature Schematic overview
Reviews of thePrimers frequency over time.
| Disease
management algorithm of diabetic macular oedema16. OCT, optical coherence Anti-VEGF therapy has also been used as a potential
tomography; VEGF, vascular endothelial growth factor. treatment for proliferative DR. The DRCRnet recently
presented the results of a non-inferiority trial compar-
3 years148. Retreatment is necessary in most patients; ing panretinal laser photocoagulation and intravitreal
most patients received on average four injections over ranibizumab among patients with proliferative DR20. At
the study period (3 years). Iluvien (Alimera Sciences, 2 years, mean improvement in visual acuity was similar
Alpharetta, Georgia, USA), another sustained-release between the two treatment modalities. Although longer-
intravitreal implant, provides a therapeutic effect of up term outcomes are unclear, these results do suggest that
to 36 months by delivering sustained sub-microgram anti-VEGF therapy might be an alternative treatment for
levels of fluocinolone acetonide (a corticosteroid). The proliferative DR.
implant can be injected through the back of the eye In terms of safety, most clinical trials reported a
with a 25‑gauge needle. The Fluocinolone Acetonide favourable safety profile for anti-VEGF agents. Ocular
in Diabetic Macular Edema149 study demonstrated that safety profiles based on various DME trials have been
in people with chronic DME for 3 years or longer, more consistent with anti-VEGF injections for other indica-
patients treated with Iluvien had an improvement of tions. In particular, rates of procedure-related serious
≥15 letters after 36 months treatment than in the sham adverse events, such as endophthalmitis and traumatic
group (28.7% versus 18.9%)149. cataract, are low. However, long-term intravitreal injec-
tions of anti-VEGF agents could lead to the neuro
Intraocular anti-VEGF agents degeneration of the remaining healthy retina and to an
Angiogenesis is a key common pathway of DR, par- increased risk of circulation disturbances in the chorio
ticularly in severe stages of DR, including DME and capillaris161. There were also concerns regarding the
proliferative DR. The development of anti-VEGF systemic safety of anti-VEGF therapy 162, particularly as
therapy has therefore been one of the most profound patients with diabetes have multiple comorbidities and
advances in ophthalmology 15,150–152. There are currently have increased cardiovascular risk163. Up to 40–50% of
three commonly used anti-VEGF agents: ranibizumab, patients with DME may need bilateral ocular therapy,
bevacizumab and aflibercept. thus potentially increasing the drug concentration in the
For DME, pivotal clinical trials have demonstrated systemic circulation164. Although no significant safety
the superior visual acuity outcome of anti-VEGF concern has been raised from the large-scale clinical
therapy compared to laser photocoagulation for the trials, these studies do not have adequate power to detect
treatment of DME145,146,153–158 (FIG. 5; TABLE 2). Although small changes in the risk of rare events such as stroke or
multiple intraocular injections (between 6 and 12) over vascular death162,165. Continued vigilance from clinicians
the first 12 months are needed, there are differences in and collection of real-life data from post-marketing sur-
retreatment protocols over this period (such as fixed veillance are necessary to further clarify the safety profile
monthly dosing versus treatment based on clinical of anti-VEGF treatments in patients with diabetes.
parameters) and intensity between individual stud-
ies, leading to different levels of visual improvement Vitrectomy
reported. In 2015, the DRCRnet reported the 12‑month In a small proportion of people with advanced dis-
results of a study that compared, head-to-head, the ease, such as those with severe proliferative DR who
relative efficacy and safety of the three commonly used do not respond to panretinal laser photocoagulation
anti-VEGF agents159. All three agents improved vision and intravitreal anti-VEGF therapy, or those who have
in patients who have DME involving the foveal centre, persistent vitreous haemorrhage and/or traction retinal
and were well tolerated. However, aflibercept was more detachment, ocular surgery involving the removal of the
effective in improving vision in eyes with poorer initial vitreous body (termed vitrectomy) may be needed3.

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PRIMER
There are multiple ways to measure HR‑QOL.

Principally, these include patient preferences, quality-
n–x Elimination of diabetic retinopathy adjusted life years (QALY)-validated instruments such
(maintained health and/or vision), but as EQ‑5D and decision analyses based on these inputs173.
patient accepts shorter duration of life Patient preferences aim to quantify HR‑QOL through
the use of two theoretical constructs: the standard refer
Current health
and/or vision ence gamble or the time trade-off technique. In the
n former model, individuals are asked to consider either
living life in their present state (in this case DR) or opt-
ing for an experimental treatment with some degree of
risk. Research based on this model demonstrates that
Diabetic retinopathy, people are willing to take a 50% risk of death to eliminate
but longer duration of life
Deterioration of their DR171. In the time trade-off model, people are asked
health and/or vision whether they are willing to live with their present con-
Remaining lifetime dition for an additional set number of years (frequently
10 years) or opt for a shorter life with their condition
Figure 7 | Time trade-off technique to evaluate quality of life. The time trade-off eliminated. Research based on this model shows that
technique is a method to elicit patient preferences. In this Nature Reviews
scenario, | Disease
a patient withPrimers patients with DR are willing to accept a 20–30% shorter
diabetic retinopathy (DR) is asked to trade-off between their current level of health for a life if their condition could be eliminated169,170 (FIG. 7).
defined period of time (n), or perfect vision or health but for a reduced length of time In terms of the use of QALY to measure HR‑QOL,
(n − x). When the patient has no preference for one of the two options — for instance,
a multi-attribute utility (with utility defined as a cardi-
7 years in perfect health and 10 years in their current state — a utility, or numerical
estimate of quality of life, is quantified (0.7 in this case). Research has shown that the
nal value that represents the strength of an individual’s
average patient with DR is willing to trade-off between 20 and 30% of their remaining life preference for a specific health outcome) instrument
to eliminate their ocular disease; their utilities are estimated at 0.7–0.8 (REFS 170,197). such as the EQ‑5D or regression equation based on visual
acuity is another way to calculate QALY174. However,
research into the impact of DR on HR‑QOL by employ-
Treatment guidelines ing EQ‑5D has produced inconsistent findings. This
With new therapies now available, guidelines on the inconsistency could be due to a lack in sensitivity of the
management of DR and DME are evolving 16,109,166,167 generic utility measures used to evaluate the specific
(FIG. 6). If DME involves the fovea centre with vision burden of DR‑induced vision loss.
loss, anti-VEGF therapy is considered the first-line treat- Estimation of utilities is also important in deriving the
ment 16,166,167. However, focal laser coagulation remains inputs for cost–utility analyses (aimed at calculating
a useful mode of treatment for DME not involving the the cost per QALY), which are mathematical models to
foveal centre. Intraocular steroids could be used as a determine incremental benefits of a new treatment ver-
second-line therapy for cases that do not respond to sus incremental costs. Research shows that treatments
these therapies. For proliferative DR and in certain cases including laser photocoagulation and anti-VEGF ther-
of severe non-proliferative DR, panretinal laser photo apy both improve quality of life and are cost-effective19.
coagulation continues to be the treatment of choice, until Intravitreal ranibizumab confers an 11% improvement
longer term results of trials using anti-VEGF therapy in quality of life and saves society money through a
are available109. reduction in falls, in rates of depression and in nursing
The choice of which anti-VEGF agent to use for home admissions, among others19.
patients with DME should be individualized to health-care
systems, patient preference and cost. No evidence exists Outlook
that specific patient characteristics, systemic conditions Despite improvements in diabetes care, increasing access
or medication use influences choice of therapy. However, to screening for diabetes and DR, and effective systemic
patients with recent cardiovascular events should be aware and ocular treatments, the public health burden of DR
of possible increased risks of stroke or vascular disease continues to be substantial. The number of people with
associated with anti-VEGF therapy, although there is no DR is likely to continue to rise owing to population
robust evidence to support this concern168. growth, ageing demographics and the expanding dia
betes epidemic worldwide. A review using published esti-
Quality of life mates from studies from 91 countries suggests that nearly
The impact of DR and associated visual impairment on 440 million people between the ages of 20 and 79 years
health-related quality of life (HR‑QOL) is substantial. will suffer from diabetes (prevalence 7.7%) by 2030,
Patients with DR have reduced physical, emotional and largely driven by an increase in the diabetes prevalence in
social well-being, and use many health-care resources6. developing nations, including those in Asia and Africa1.
Numerous studies have estimated that DR reduces Although laser photocoagulation therapy has long
HR‑QOL by 20–30% when it affects the eye with worse been the standard of care for managing DME and
vision, and up to 50% if it affects the eye with better vision, proliferative DR142,143, the development and application
compared with persons with diabetes without DR17,169,170. of intravitreal anti-VEGF agents has heralded a new
Patients with diabetes estimate a 60% reduction in treatment paradigm for DME, with the potential to
HR‑QOL if they were to develop blindness171,172. dramatically improve vision and quality of life3,14,16,159,175,

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PRIMER
and potentially for proliferative DR20. Given that anti- As discussed in this Primer, the development of DR
VEGF agents are costly and require repeat applications, is strongly influenced by diabetes duration, and systemic
the economic burden for both patients and the society control of glycaemia and blood pressure9. Optimal con-
is substantial176. Considerable savings of 40–90% could trol of glycaemia and blood pressure is critical for pre-
potentially be achieved with a less costly drug, when less- venting DR development in primary care settings128,129,134.
costly drugs of similar efficacy are used in a personal- Although international guidelines recommend that
ized approach to manage DME177. Bevacizumab confers patients with T1DM should be screened 5 years from
greater cost-effective value among the currently available diagnosis and those with T2DM at the time of diagno-
anti-VEGF agents for DME, as ranibizumab and afliber- sis109, only half of patients receive appropriate screen-
cept are substantially more expensive than bevacizumab ing 186. Moreover, patients’ understanding of diabetes and
in some countries178. Furthermore, anti-VEGF therapy DR, the importance of systemic control, and utilization
poses considerable challenges in developing countries. of health-care services is low in the United States and
What are avenues for further research? Clinical other countries187–189. Systems that facilitate seamless
trials are ongoing to evaluate anti-VEGF treatments for communication between primary care providers, intern-
DME eyes with very good visual acuity and for redu ists, optometrists and ophthalmologists are crucial to
cing DR progression (TABLE 2). Importantly, anti-VEGF ensure that diabetes care is patient-centric, holistic and
monotherapy for DME is not a cure, and new thera- comprehensive. Thus, broad, integrated public health-
peutics targeted at other mechanisms are needed179. care programmes that combine DR screening with
Apart from neovascularization, several other mech- raising awareness, public education and appropriate sys-
anisms are important in the pathogenesis of DR (that temic control of glycaemia and blood pressure are likely
is, neurodegeneration, neuroinflammation and renin– to have greater impact than just the provision of tertiary
angiotensin). Experimental therapies targeting these DR care21,109,190,191. Indeed, data from western populations
pathways have been shown to have positive effects180, but are starting to show a reduction in DR progression and
more research is clearly needed in this area. Emerging vision loss based on broad measures44.
research into systemic (for example, microRNA, pro- In conclusion, DR is an increasingly common global
teomics and metabolomics) and vitreous biomarkers clinical and public health condition that exerts a con-
may uncover additional novel pathways181,182. siderable effect on patients and society. New thera-
The increasing use of advanced OCT technology pies such as anti-VEGF treatments have been a major
(for example, new higher resolution OCT) has also breakthrough in the management of vision-threatening
allowed more precise qualitative and quantitative assess- stages of DR; indeed, anti-VEGF therapies are now first-
ment of structural changes in DME183. OCT enables line therapies for DME. However, issues related to the
the objective monitoring of treatment response and cost-effectiveness of anti-VEGF treatment and access to
prognostication (for example, disruption of outer retinal this treatment in developing nations remain. Improved
layers may indicate poor prognosis)184. Newer technol understanding of the underlying pathophysiological
ogies such as OCT angiography (which also measures mechanisms of DR to find innovative strategies for its
retinal blood flow) may facilitate the assessment of both screening and early treatment would be important to
structural and functional changes in DR185. prevent DR‑associated blindness.
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PRIMER
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trials of anti-VEGF agents for diabetic retinopathy. to incidence and progression of diabetic retinopathy Acknowledgements
Graefes Arch. Clin. Exp. Ophthalmol. 248, 915–930 in type 1 diabetes. Diabetes 65, 216–227 (2016). This paper was supported by a National Medical Research
(2010). 183. Yeung, L., Lima, V. C., Garcia, P., Landa, G. Council Grant (STaR Award 2013).
165. Thulliez, M. et al. Cardiovascular events and bleeding & Rosen, R. B. Correlation between spectral domain
risk associated with intravitreal antivascular optical coherence tomography findings and fluorescein Author contributions
endothelial growth factor monoclonal antibodies: angiography patterns in diabetic macular edema. Introduction (T.Y.W.); Epidemiology (T.Y.W.); Mechanisms/
systematic review and meta-analysis. Ophthalmology 116, 1158–1167 (2009). pathophysiology (R.S.); Diagnosis, screening and prevention
JAMA Ophthalmol. 132, 1317–1326 (2014). 184. Maheshwary, A. S. et al. The association between (M.L.); Management (C.M.G.C.); Quality of life (S.S.); Outlook
166. Bandello, F. et al. New approaches for the treatment percent disruption of the photoreceptor inner (S.S.); overview of Primer (T.Y.W.).
of diabetic macular oedema: recommendations segment–outer segment junction and visual acuity
by an expert panel. Eye 26, 485–493 (2012). in diabetic macular edema. Am. J. Ophthalmol. 150, Competing interests statement
167. Thomas, B. J., Shienbaum, G., Boyer, D. S. & 63–67 e1 (2010). T.Y.W. is on advisory boards for Abbott, Allergan, Bayer,
Flynn, H. W. Jr. Evolving strategies in the management 185. Ishibazawa, A. et al. Optical coherence tomography Novartis, Pfizer and Solvay, and has received travel, honoraria
of diabetic macular edema: clinical trials and current angiography in diabetic retinopathy: a prospective and research support from these companies. He has no stocks,
management. Can. J. Ophthalmol. 48, 22–30 (2013). pilot study. Am. J. OphthalmoL. 160, 35–44 (2015). equity, contract of employment or named positions on company
168. Avery, R. L. & Gordon, G. M. Systemic safety of 186. Lee, P. P., Feldman, Z. W., Ostermann, J., Brown, D. S. boards. C.M.G.C. is on advisory boards for Allergan, Bayer and
prolonged monthly anti-vascular endothelial growth & Sloan, F. A. Longitudinal rates of annual eye Novartis, and has received travel, honoraria and research
factor therapy for diabetic macular edema: examinations of persons with diabetes and chronic eye support from these companies. She has no stocks, equity,
A systematic review and meta-analysis. diseases. Ophthalmology 110, 1952–1959 (2003). contract of employment or named positions on company
JAMA Ophthalmol 134, 21–29 (2015). This study demonstrates that over a 9‑year period, boards. M.L. is on advisory boards for Allergan, Bayer and
169. Brown, M. M., Brown, G. C., Sharma, S., Landy, J. only just over half of patients with chronic eye Novartis, and has received travel, honoraria and research
& Bakal, J. Quality of life with visual acuity loss from diseases, including diabetes, complied with support from these companies. He has no stocks, equity,
diabetic retinopathy and age-related macular practice guidelines. contract of employment or named positions on company
degeneration. Arch. Ophthalmol. 120, 481–484 187. Bressler, N. M. et al. Underuse of the health care boards. S.S. has served on advisory boards for Allergan, Alcon,
(2002). system by persons with diabetes mellitus and Novartis, Pfizer, Bayer and eSight. He has received travel,
170. Sharma, S. et al. Utilities associated with diabetic diabetic macular edema in the United States. honoraria or research support from these companies. He has
retinopathy: results from a Canadian sample. JAMA Ophthalmol. 132, 168–173 (2014). no stocks, equity, contract of employment or named positions
Br. J. Ophthalmol. 87, 259–261 (2003). This study, based on the US National Health and on company boards. R.S. is on advisory boards of Allergan,
171. Huang, E. S., Brown, S. E., Ewigman, B. G., Foley, E. C. Nutrition Examination Survey conducted between Novo Nordisk and Eli Lilly and Company. In addition, he has
& Meltzer, D. O. Patient perceptions of quality of life 2005 and 2008, showed that a high proportion of received travel and research support from Abbott, Sanofi-
with diabetes-related complications and treatments. people with diabetes in the United States did not Aventis and Astra Zeneca. He has no stocks, equity, contract of
Diabetes Care 30, 2478–2483 (2007). have screening. employment or named positions on company boards.

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CORRECTION
CORRIGENDUM
Diabetic retinopathy
Tien Y. Wong, Chui Ming Gemmy Cheung, Michael Larsen, Sanjay Sharma and Rafael Simó
Nature Reviews Disease Primers article number: 16012; doi:10.1038/nrdp.2016.12; published online 17 March 2016
The affiliation for Sanjay Sharma has now been corrected: Departments of Ophthalmology and Epidemiology,
Queen’s University, Kingston, Ontario, Canada.
NATURE REVIEWS | DISEASE PRIMERS www.nature.com/nrdp

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PRIMER

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 1

Author addresses Epidemiology

Non-proliferative diabetic retinopathy Pre-proliferative retinopathy

Cornea Lens Retina

Diabetic macular oedema Proliferative retinopathy

2 | 2016 | VOLUME 2 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 3

4 | 2016 | VOLUME 2 www.nature.com/nrdp

IPL Severe non-proliferative DR. In later stages of non-­

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 5

6 | 2016 | VOLUME 2 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 7

HbA1c (for example, from 9% to 8%) lowers the risk

8 | 2016 | VOLUME 2 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 9

Laser photocoagulation injections are usually performed in office settings

10 | 2016 | VOLUME 2 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 11

There are multiple ways to measure HR‑QOL.

12 | 2016 | VOLUME 2 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 13

14 | 2016 | VOLUME 2 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 15

16 | 2016 | VOLUME 2 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS www.nature.com/nrdp

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IPL Severe non-proliferative DR. In later stages of non-