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.

Correspondence to T.Y.W.
Singapore Eye Research
Institute, Singapore National
Eye Centre, 11 Third Hospital
Avenue, Singapore 168751,
Singapore.
wong.tien.yin@snec.com.sg
Article number: 16012
doi:10.1038/nrdp.2016.12
Published online 17 March 2016;
corrected online 7 April 2016
Diabetes mellitus is a global epidemic with profound
morbidity 1. Diabetes leads to a range of complications
grouped into macrovascular (large blood vessel) compli-
cations, such as cardiovascular disease and stroke, and
microvascular (small blood vessel) complications, such
as kidney disease. Diabetic retinopathy (DR) is a specific
microvascular complication of diabetes and is the lead-
ing cause of vision loss in the general population in many
countries, including the adult working population and
the elderly 2–5. Patients with severe degrees of DR have
impaired quality of life, reduced physical, emotional and
social well-being, and use many health-care resources6.
Without treatment, DR progresses from mild,
non-proliferative DR to moderate and severe non-­
proliferative DR before the occurrence of proliferative
DR, in which there is growth of abnormal new retinal
blood vessels. Concurrently, at any stage of retinopathy,
with exudation and oedema at the macula (the central
focal point of the retina), patients may also develop
­diabetic macular oedema (DME) (FIG. 1; TABLE 1).
Although DR is present in approximately 30% of
individuals with diabetes, only 5–10% may have the
sight-threatening stages of proliferative DR and DME7,8.
However, the individual lifetime risk of DR is 50–60% in
a person with type 2 diabetes mellitus (T2DM) and up to
90% in those with type 1 diabetes mellitus (T1DM)9,10.
A pooled meta-analysis11 of 35 population-based (mostly
from developed countries) studies reported that more
than 90 million individuals are estimated to have DR, with
21 million having DME and 17 million proliferative DR.
There has been considerable progress in understand-
ing the key pathogenetic factors involved in the develop­
ment of DR. Although DR is traditionally regarded as a
microvascular disease, growing evidence supports the
idea that retinal neurodegeneration is an early event in
the pathogenesis of DR. For example, a reduction in the
oscillatory potential in electroretinogram tests is the first
­m easurable change in retinal function in patients
with diabetes12.
Past epidemiological studies and clinical trials have
shown that the development risk and progression of
DR can be reduced by controlling blood glucose levels
and blood pressure2,13. Landmark clinical trials in the
1980s and 1990s have also demonstrated that timely
laser photo­coagulation can prevent moderate to severe
vision loss in patients with DME or proliferative DR2,13–15.
In the 2000s, the introduction of intraocular adminis-
tration of anti-vascular endothelial growth factor (anti-
VEGF) agents and fast, non-invasive imaging in the
form of optical coherence tomography (OCT) further
revolutionized the management of DME, resulting in
the possibility of reversing vision loss2,3,15,16. Anti-VEGF

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Author addresses Epidemiology

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

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

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

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

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

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

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

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robust. In the UKPDS, tighter blood pressure control
(target blood pressure of <150/85 mm Hg versus a less
tight control target of <180/105 mm Hg) reduced the
risks of DR progression and need for laser treatment
by approximately one-third and vision loss by 50%
in T2DM129. However, in contrast to glycaemic con-
trol, these benefits are not sustainable (no ‘memory’)
without ongoing and long-term maintenance of blood
­pressure control134.
Certain blood pressure-lowering medications, par-
ticularly those targeting the RAS, can exert beneficial
actions other than lowering the blood pressure level.
The EURODIAB controlled trial of lisinopril (an
angiotensin-converting enzyme inhibitor) in insulin-­
dependent diabetes (EUCLID) study investigated the
effect of lisinopril on retinopathy in non-hypertensive
patients with T1DM who were normoalbuminuric or
microalbuminuric. One hundred and seventeen patients
were randomly assigned to the placebo group and
103 patients were randomized to the lisinopril group.
The results showed that lisinopril reduced the risk of
DR and proliferative DR progression by 50% and 80%,
respectively 135. However, the EUCLID study had limi-
tations in terms of differences in baseline glycaemia in
a from two independent randomized trials suggests that
Cystoid
spaces Nerve
Inner limiting membrane Inner nuclear layer fibre layer
Inner plexiform layer
Outer plexiform layer
Retina pigment epithelium
Choroid
Outer nuclear layer
b Cystoid
spaces
c ins to evaluate the effect of this combination on DR132.
Intraretinal
cysts
the control versus treated group, and its short (2‑year)
follow‑up. The Diabetic Retinopathy Candesartan Trials
(DIRECT) programme examined effects of candesar­
tan (an angiotensin receptor blocker) in T1DM 136
and T2DM 136,137. In T1DM, 5  years of ­c andesartan
treatment resulted in a reduction in the incidence of
DR compared to placebo (hazard ratio of 0.82), but
no beneficial effect on DR progression in those with
pre-existing DR was observed136. In T2DM with mild
to moderate DR, 5 years of candesartan treatment
resulted in DR regression by 34%137. An overall change
towards less severe DR was observed in the candesartan
group in T2DM. The Renin Angiotensin System Study
(RASS) evaluated the effect of enalapril (an angio­tensin
convert­ing enzyme inhibitor) and losartan (an angio-
tensin receptor blocker) on DR ­progression in T1DM138.
After 5 years, the risk of DR progression was reduced
by 65% with enalapril and 70% with losartan, indepen­
dent of blood pressure. These trials suggest that specific
drugs that target the RAS may be superior to stand-
ard blood ­pressure-lowering medications in reducing
retinopathy risk.
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
fenofibrate could reduce the risk of vision-­threatening
DR in T2DM. The Fenofibrate Intervention and Event
Lowering in Diabetes study assessed the effects of
fenofibrate on cardiovascular outcomes in patients
with T2DM who did not take statins139. Laser treatment
for DR, a pre-specified tertiary outcome, was reduced
by 37% in the fenofibrate group compared to a pla-
cebo group after 5 years. The number needed to treat
with fenofibrate to prevent laser treatment was only
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-
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.

Figure 5 | Optical coherence tomography showing treatment outcomes
Nature Reviews for Primers
| Disease
diabetic macular oedema. Optical coherence tomography (OCT) images of a
patient with type 2 diabetes with diabetic macular oedema (DME). a | OCT image of
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
spaces before intravitreal injections of ranibizumab (an anti-vascular endothelial growth
factor therapy) were started. b | Vision of 6/18 (that is, vision improved from 6/45 to 6/18)
was observed after three intravitreal injections of ranibizumab. c | Vision of 6/9 (that is,
vision improved from 6/18 to 6/9, almost normal vision) was observed after seven
intravitreal injections of ranibizumab.
Management
Vision loss as a consequence of severe DR can be mini­
mized by intervention using intraocular anti-VEGF
agents for DME, panretinal laser photo­coagulation
for proliferative DR, and vitrectomy for vitreous
haemor­rhage and traction retinal detachment 3,14–16,109.
Intravitreal anti-VEGF therapy has also been shown to
reduce the level of DR141, and its potential utility for treat-
ment of proliferative DR has now been ­demonstrated in
recent clinical trials20.

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Laser photocoagulation injections are usually performed in office settings

For almost three decades, laser photocoagulation has
been the standard ocular treatment for proliferative DR
and DME14,15. The mechanism of action of laser photo-
coagulation is not fully understood, but one hypothesis
is that laser photocoagulation-induced scars alleviate
hypoxia and affects the haemodynamics of the retinal
circulation. Improved retinal oxygenation reduces neo-
vascularization and oedema formation by reducing the
production of VEGF and other factors, and by trigger­
ing haemodynamic changes14. The primary goal for
most patients receiving laser therapy is to preserve use-
ful vision and prevent blindness, and reversal of vision
loss is uncommon.
Two landmark trials provided the evidence for the
use of laser photocoagulation for DR. The Diabetic
Retinopathy Study (DRS) demonstrated that pan­
retinal laser photocoagulation reduced the risk of
severe vision loss from 33.0% to 13.9% at 5  years
in patients with proliferative DR or severe non-­
proliferative DR 142. The Early Treatment Diabetic
Retinopathy Study (ETDRS) demonstrated that focal
laser photocoagulation reduced the risk of vision loss
in patients with clinically significant DME from 24%
to 12%, but did not eliminate this risk142,143. However,
only 3% of patients had a significant improvement in
visual acuity, which is partly explained by the ceiling
effect caused by the relatively good baseline vision
in the study population. Furthermore, laser photo­
coagulation itself is associated with significant ocular
side effects due to its inherent destructive nature to the
retina, including induction of scotoma (that is, a blind
spot), enlargement of laser scars and ­development of
secondary neovascularization.
Intraocular steroids
In the 2000s, intraocular administration of steroids and
anti-VEGF agents were introduced as new treatment
modalities for DME and proliferative DR. Intraocular
by ophthalmologists using an aseptic technique and
­topical anaesthesia.
The activation of inflammatory pathways has been
proposed as one of the mechanisms in DME patho-
genesis. Corticosteroids suppress multiple pathways of
inflammation and have been advocated as a treatment
option for DME, particularly in cases refractory to laser
photocoagulation. In addition, corticosteroids down-
regulate VEGF expression144 and reduce the induction
of VEGF by pro-inflammatory mediators. However, the
introduction of anti-VEGF agents confined the use of
corticosteroids to selected patients, such as those with
previous cataract surgery and with chronic DME.
Off-label use of triamcinolone (a long-acting
cortico­steroid) has been shown to reduce DME and to
improve vision in the short-term145. The DR Clinical
Research Network (DRCRnet) reported that the bene-
fits of intravitreal triamcinolone did not persist beyond
1 year, and by 2 years the visual outcome was generally
not better than laser photocoagulation146. Importantly,
considerable adverse effects (such as cataract and
glaucoma) are common. In addition, there are con-
cerns of increased risk of infectious endophthalmitis
(an eye infection) owing to the immunosuppressive
properties of corticosteroid and also sterile (non-­
infectious) endophthalmitis, which may be precipi-
tated by additives in the t­ riamcinolone preparation or
bacterial endotoxins147.
Two sustained-release intravitreal implants have
recently been evaluated for DME. Ozurdex (Allergan,
Irvine, California, USA) is a biodegradable implant
that is inserted using a 22‑gauge applicator and
releases 0.7 mg of dexamethasone over 120–180 days.
In one trial, significantly more patients in the Ozurdex
group achieved ≥15 letter improvement (improve-
ment in ~3 lines on the standard Snellen visual acuity
chart) in best corrected visual acuity compared with
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.

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

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 PRIMER

and potentially for proliferative DR20. Given that anti-
VEGF agents are costly and require repeat applications,
the economic burden for both patients and the society
is substantial176. Considerable savings of 40–90% could
potentially be achieved with a less costly drug, when less-
costly drugs of similar efficacy are used in a personal-
ized approach to manage DME177. Bevacizumab confers
greater cost-effective value among the currently available
anti-VEGF agents for DME, as ranibizumab and afliber-
cept are substantially more expensive than bevacizumab
in some countries178. Furthermore, anti-VEGF therapy
poses considerable challenges in developing countries.
What are avenues for further research? Clinical
­trials are ongoing to evaluate anti-VEGF treatments for
DME eyes with very good visual acuity and for redu­
cing DR progression (TABLE 2). Importantly, anti-VEGF
monotherapy for DME is not a cure, and new thera-
peutics targeted at other mechanisms are needed179.
Apart from neovascularization, several other mech-
anisms are important in the pathogenesis of DR (that
is, neuro­degeneration, neuroinflammation and renin–­
angiotensin). Experimental therapies targeting these
pathways have been shown to have positive effects180, but
more research is clearly needed in this area. Emerging
research into systemic (for example, microRNA, pro-
teomics and metabolomics) and vitreous biomarkers
may uncover additional novel pathways181,182.
The increasing use of advanced OCT technology
(for example, new higher resolution OCT) has also
allowed more precise qualitative and quantitative assess-
ment of structural changes in DME183. OCT ­enables
the objective monitoring of treatment response and
prognosti­cation (for example, disruption of outer retinal
layers may indicate poor prognosis)184. Newer techno­l­
ogies such as OCT angiography (which also measures
retinal blood flow) may facilitate the assessment of both
structural and functional changes in DR185.
As discussed in this Primer, the development of DR
is strongly influenced by diabetes duration, and systemic
control of glycaemia and blood pressure9. Optimal con-
trol of glycaemia and blood pressure is critical for pre-
venting DR development in primary care settings128,129,134.
Although international guidelines recommend that
patients with T1DM should be screened 5 years from
diagnosis and those with T2DM at the time of diagno-
sis109, only half of patients receive appropriate screen-
ing 186. Moreover, patients’ understanding of diabetes and
DR, the importance of systemic control, and utilization
of health-care services is low in the United States and
other countries187–189. Systems that facilitate seamless
communication between primary care providers, intern-
ists, optometrists and ophthalmologists are crucial to
ensure that diabetes care is patient-centric, holistic and
comprehensive. Thus, broad, integrated public health-
care programmes that combine DR screening with
raising awareness, public education and appropriate sys-
temic control of glycaemia and blood pressure are likely
to have greater impact than just the provision of tertiary
DR care21,109,190,191. Indeed, data from western populations
are starting to show a reduction in DR progression and
vision loss based on broad measures44.
In conclusion, DR is an increasingly common global
clinical and public health condition that exerts a con-
siderable effect on patients and society. New thera-
pies such as anti-VEGF treatments have been a major
breakthrough in the management of vision-threatening
stages of DR; indeed, anti-VEGF therapies are now first-
line therapies for DME. However, issues related to the
cost-effectiveness of anti-VEGF treatment and access to
this treatment in developing nations remain. Improved
understanding of the underlying pathophysiological
mechanisms of DR to find innovative strategies for its
screening and early treatment would be important to
prevent DR‑associated blindness.

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PRIMER

155. Massin, P. et al. Safety and efficacy of ranibizumab
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Acknowledgements
This paper was supported by a National Medical Research
Council Grant (STaR Award 2013).
Author contributions
Introduction (T.Y.W.); Epidemiology (T.Y.W.); Mechanisms/
pathophysiology (R.S.); Diagnosis, screening and prevention
(M.L.); Management (C.M.G.C.); Quality of life (S.S.); Outlook
(S.S.); overview of Primer (T.Y.W.).
Competing interests statement
T.Y.W. is on advisory boards for Abbott, Allergan, Bayer,
Novartis, Pfizer and Solvay, and has received travel, honoraria
and research support from these companies. He has no stocks,
equity, contract of employment or named positions on company
boards. C.M.G.C. is on advisory boards for Allergan, Bayer and
Novartis, and has received travel, honoraria and research
support from these companies. She has no stocks, equity,
contract of employment or named positions on company
boards. M.L. is on advisory boards for Allergan, Bayer and
Novartis, and has received travel, honoraria and research
support from these companies. He has no stocks, equity,
contract of employment or named positions on company
boards. S.S. has served on advisory boards for Allergan, Alcon,
Novartis, Pfizer, Bayer and eSight. He has received travel,
honoraria or research support from these companies. He has
no stocks, equity, contract of employment or named positions
on company boards. R.S. is on advisory boards of Allergan,
Novo Nordisk and Eli Lilly and Company. In addition, he has
received travel and research support from Abbott, Sanofi-
Aventis and Astra Zeneca. He has no stocks, equity, contract of
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.

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