Cover Page

Designer to create

1
Working Group
Chair:
Dr. Shaukat Sadikot, Jaslok Hospital and
Research Center, Mumbai, India; Diabetes
India
Core Contributors:
Prof. Anat Lowenstein, Ophthalmology
Division, Tel Aviv Medical Center, affiliated to
the Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel.
Prof. Gavin Tan, Singapore National Eye Centre
& Singapore Eye Research Institute; Eye
Academic Clinical Program, Duke-NUS
Graduate Medical School, Singapore.
Prof. Weiping Jia, Shanghai Diabetes Institute,
Shanghai Clinical Center for Diabetes, Shanghai
Jiao Tong University Affiliated Sixth People’s
Hospital, Shanghai, China.
Prof. Marco Dutra Medeiros, Department of
Ophthalmology - Portuguese Diabetes
Association; Department of Ophthalmology -
Central Lisbon Hospital Center; NOVA Medical
School - Universidade NOVA de Lisboa,
Portugal.
Dr. Luis Gardete Correia, Associação Protectora
dos Diabéticos de Portugal (APDP), Lisbon,
Portugal.
Dr. Dinah Zur, Ophthalmology Division, Tel Aviv
Medical Center, affiliated to the Sackler Faculty
of Medicine, Tel Aviv University, Tel Aviv, Israel.
Acknowledgements:- Insignia Learning Pvt. Ltd.,
India
IDF Executive Office – Belgium
Lisa Duke, …
Duality of interest statement:
All members of the guidelines working group
declared dualities of interest in respect to
commercial enterprises, governments and non-
governmental organisations. No fees were paid
to Working Group members in connection with
the current activity.
Copyright
All rights reserved. No part of this publication
may be reproduced or transmitted in any form
or by any means without the written prior
permission of the
IDF. Requests to reproduce or translate IDF
publications should be addressed to
communications@idf.org
© International Diabetes Federation 2019
Publisher:International Diabetes Federation
ISBN: Comms team to update
Please cite this report as:
International Diabetes Federation. to be update
Correspondence:
International Diabetes Federation,
166 Chaussée de La Hulpe,
B-1170, Brussels
Belgium
communications@idf.org
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Proposed Table of Content

Foreword

Purpose and Scope of this document

1. Introduction to DME

1.1 Definition of the Problem

1.2 Classification of DME

1.3 Prevalence and Incidence of DME

2. Risk Factors of DME

2.1 Hyperglycaemia

2.2 Hypertension

2.3 Dyslipidaemia

2.4 Duration of DM

2.5 DR

2.6 Obesity

2.7 Cataract Surgery

2.8 Sleep Apnoea

2.9 Pregnancy

3. Screening of DME

3.1 Retinal Examination

3.2 Examination Method

3.3 When to Refer to an Ophthalmologist

3.4 Re-examination and Referral Recommendations

4. Treatment of DME

4.1 Ocular-based Therapies

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 4.2 Intravitreal Injections

4.3 Polytherapy

4.4 Surgical Approaches

5. Systemic Management of DME

6. Patient Communication and Education

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FOREWORD

Diabetes Mellitus (DM) directly affects the lives of an estimated 425 million people worldwide (adults
aged from 20-79 years). Diabetes disproportionately afflicts people in low- and middle-income
countries. By 2040, 642 million people, or 1 in 10 adults across the globe, will live with diabetes.1

With these growing trends, more and more people also live with complications that directly result from
diabetes. Some complications are truly life-threatening, while others are so debilitating that they
severely curtail a person’s day-to-day activities and quality of life.

Diabetic retinopathy (DR) is a complication of diabetes that, while unnoticeable in its early stages, can
lead to vision impairment and blindness. It affects an estimated one third of all people with diabetes,
and is a leading cause of vision loss and blindness in the working age population.2 With the risk
exacerbated by hypertension and dyslipidemia, chronic hyperglycemia causes damage to the retinal
capillaries.3 In fact, as found by International Diabetes Federation (IDF) in the 2015 DR Barometer,
79% of respondents with diabetes said their vision impairment due to DR or Diabetic Macular Edema
(DME) made everyday activities difficult, such as driving, working and cooking or cleaning their home,
and in some cases impossible.4 A further important complication of diabetes, DME is assessed
separately from DR, since it can occur in eyes at any DR severity level.5

Therefore, early screening and detection is crucial in arresting and possibly correcting DME. Because
the early damage is painless and unnoticed by the patient, regular screening of all individuals with
diabetes is recommended. Yet, nearly one-third of health practitioners reported needing additional
training in the diagnosis, treatment, and referral of diabetic eye disease.6 Due to its threat to vision,
the clinical signs of DME warrant immediate referral to an ophthalmologist.7 As such, the utilization of
trained health care professionals to carry out basic screening and to make appropriate referrals would
be the most efficient use of resources.8

In support of those on the frontline of diabetic eye health, IDF has led a team of experts in the
development of the current IDF Clinical Practice Recommendations for Managing Diabetic Macular
Edema. This decision support tool will facilitate the work of general practitioners, hospital-based
clinicians, and other primary health care clinicians working in diabetic eye disease management.

These clinical recommendations grew out of a highly collaborative, evidence-based process. They
represent the latest advances in DME management.

On behalf of the International Diabetes Federation, we would like to thank the technical working
group, led by Dr. Shaukat Sadikot, all the experts, reviewers, and editors who have endeavored to
make these recommendations a reality. Thanks to their attention to detail, these clinical practice
recommendations have become a truly practical guide for clinicians. Therefore, we wish to express our
sincere gratitude and appreciation for their contributions.

This clinical practice recommendation supports clinicians caring for their patients with diabetes. We
salute their efforts to protect their patients’ vision.

Dr. Shaukat Sadikot Prof. Nam H Cho

IDF President (2016-2017) IDF President (2018-2019)

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1. INTRODUCATION TO DME
Diabetic macular edema (DME) is a complication of diabetic retinopathy (DR) and all people with
diabetes are at risk.

The increasing and wider availability of screening and treatment options for DR and DME offer the
possibility of early diagnosis and management, and thereby the possibility of stemming, the
consequences of vision threatening retinal complications in diabetes. The vast numbers of people with
diabetes worldwide, the availability, accessibility and affordability of the screening and management
strategies for DR and DME will inform surveillance and treatment options. The possibility of treatment,
even if easily available, may not always translate into reality.

In this Clinical Practice Recommendation, we look at the available evidence, risk factors, diagnostic,
treatment and management strategies, with the aim to alleviate this significant, but often neglected
health problem.

1.1 DEFINITION OF THE PROBLEM

Physiopathology and link between DR and DME
Diabetic Retinopathy (DR) is a significant microvascular complication of DM. It is the general descriptor
of microvascular anomalies in the fundus of the eyes in persons with diabetes.

The blood-retinal barrier (BRB), a unique feature of the eye, affects this equation. The retinal capillaries
constitute the inner BRB, and the retinal pigment epithelium comprises the outer BRB. The retinal
capillary abnormalities disrupt the inner BRB, and can affect any hydrostatic or oncotic gradients that
would normally exist. (Fig. 1)

The relationship is similar to those found in other vascular systems. In fact, the increasing intracapillary
hydrostatic forces favor the net movement of fluid into the surrounding tissues. In addition, the oncotic
pressure gradients also determine the net movement of intravascular, intercellular, and intracellular
fluid.

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This deterioration of the blood-retinal barrier results in diabetic macular edema (DME), an
accumulation of fluid within the central area of the retina. Extensive capillary leakage causes diffuse
edema, whereas focal leakage from grouped microaneurysms leads to localized edema. As the onset
of DME is usually insidious and asymptomatic, people have no warning that they have the condition
until they notice a blurring of their central vision. The severity of the condition can range from mild —
a loss of one line of vision on a standardized eye chart — to blindness.

The pathogenesis of DME is multifactorial. While vascular endothelial growth factor (VEGF) contributes
to DME development, non-VEGF pathways need to be emphasised. There is growing evidence that
inflammation plays a major role in the development and worsening of DR in general180,181 and DME in
particular.182-184

Clinically significant macular edema (CSME) describes retinal thickening and/or adjacent hard
exudates. This term is divided further into central-involving and non-central-involving macular edema,
depending on the involvement of the center of the macula or the threat to it.

Findings Observable on Dilated

Diabetic Macular Edema
Ophthalmoscopy#

No DME No retinal thickening or hard exudates in the macula

Retinal thickening in the macula that does not involve the central subfield zone that is 1mm in
Noncentral-involved DME
diameter

Retinal thickening in the macula that does involve the central subfield zone that is
Central-involved DME
1mm in diameter

# Hard exudates are a sign of current or previous macular edema. DME is defined as retinal thickening, and this
requires a three-dimensional assessment that is best performed by a dilated examination using slit-lamp bio
microscopy and/or stereo fundus photography.

1.2 CLASSIFICATION OF DME

Central-involved DME refers to the thickening or swelling of the center of the macula.

Non-central-involved DME indicates the lack involvement the center of the macula.

Fluorescent angiography (FAG) is a contrast study, which confirms the presence of DME and classifies
it as focal and diffuse. This classification influences the pathophysiology.

Focal DME results from internal BRB damage (microaneurisms).

Diffuse DME is linked mainly to external BRB damage (pigment epithelium of the retina). The main
structural change accounting for DME is the disruption of the blood-retinal barrier (BRB) brought about
by long term hyperglycaemia.64

Vascular endothelial growth factor (VEGF) is a key mediator in the pathogenesis of DME. VEGF is an
important factor for significantly increasing the vascular permeability. 142, 143 VEGF levels are

7
significantly elevated in the vitreous of patients with DME when compared with non-diabetic eye
conditions. 143

1.3. PREVALENCE AND INCIDENCE OF DME

The global prevalence of DME among individuals with T1DM and T2DM varies by geographic region,
with rates ranging from 11.4% in some European countries to as high as 45.3% in some N. African
countries.3

Data from low-income countries (LIC) is limited. A meta-analysis of 35 studies (22,896 patients from
the USA, Australia, Europe and Asia carried out by Yau et al. [META EYE Study Group]) reported a
global prevalence of DME of 7.48% (7.39-7.57%) in the overall diabetes population. Putting this
simply, one in 14 people with diabetes have some element of DME and more than 21 million people
worldwide are affected.2

A recent 10-year study concluded that 20% of patients with type 1 diabetes, and 25% of those with
type 2 diabetes, would develop DME. An important cause of vision loss experienced by people with
diabetes, DME is the primary cause among those living with type 2 diabetes and presents
consistently in those people with PDR.

In China, the rates were 3.5% in the rural areas and 2.6% in the urban populations.10 Interestingly, in
Singapore, which is newly urbanised, the prevalence rates were 5.9% for Chinese, 5.7% for Malays and
7.2% for Indian residents,11,12 again showing the importance of ethnic differences.

These differences could be due to ethnic and socioeconomic differences in the population. The
variability of the diagnostic facilities and management care available in different countries may further
influence them as well. Their affordability and accessibility in many LIC countries, especially for those
people living in remote and rural areas also can affect results.

Moreover, the definition of what constitutes clinically significant macular edema (CSME) and the
diagnostic methodology can affect prevalence prevalence. Among the population-based studies, most
studies used non-stereoscopic fundus photography, which affects the accuracy of DME assessment.
About half of the studies defined macular edema using the CSME criteria, and hence these studies
captured only the more severe spectrum of DME. Overall, the heterogeneity in methodology causes
comparison of prevalence between these studies to be a challenge.

Some studies, including one from Kenya, reported a significantly high prevalence of DME. In Kenya, a
population-based study found a prevalence of DME of 33.3 % among participants with diabetes.13 A
Cochrane review of prevalence of DME assessed by optical coherence tomography (OCT) has found a
large range of prevalence rates (19–65%).16 None of the studies included in the review were
population-based studies. OCT-detected DME was found to have a great degree of disagreement with
the clinical definition of CSME, and not all patients who had macular thickening detected on OCT
progressed to have CSME; hence its validity as a diagnostic tool in epidemiologic studies remains
questionable.

Data about the incidence of DME is limited to the US and Europe. In the USA, the WESDR (Wisconsin
Epidemiologic Study of Diabetic Retinopathy) showed a 10-year incidence of 20% for people with
T1DM and 25% for people with T2DM.17 The 25-year follow up of T1DM patients showed that 29%

8
developed DME. Most of the increase occurred in the first 15 years and then decreased possibly due
to better diabetes management or may be due to selective bias.18

2. RISK FACTORS OF DME

Diabetes duration, noted as age at diagnosis, is a strong risk factor for DME22.In pregnant women
previously diagnosed with DM, both DR and DME can progress rapidly, especially in those with T1DM.

 Modifiable and non-modifiable factors associated with the onset of DME:

o Hyperglycemia, especially in the presence of
o Hypertension
o Hyperlipidemia
o Duration of both Types 1 and 2 DM
o Gender (more frequent in males)

 Additional pre-existing conditions place a person with diabetes at greater risk for
developing DME:
o Diabetic retinopathy
o Obesity – in Type1 DM, and in non-Asian Type 2
o Previous cataract surgery
o Nephropathy / microalbuminuria
o Sleep apnoea
o Current pregnancy with pre-existing diabetes

2.1 Hyperglycaemia
Hyperglycaemia is a significant risk factor for DME, and findings from large trials show that early
intensive glycaemic control can halve the risk.24

Recommendation
The therapeutic goal of tight metabolic control should be balanced against the risk of hypoglycaemia,
especially in older people, in whom aggressive glycaemic control does not further reduce retinopathy
risk, and might even be associated with increased mortality.29 Thus, guidelines recommend an HbA1c
target of 6.5–7.5% (48–58 mmol/mol)30, but clinicians should set individualised targets on the basis of
age, disease progression, risk of hypoglycaemic episodes, and other factors.

2.2 Hypertension
Raised blood pressure is an important risk factor for DME.31 A 10 mm Hg decrease in the systolic blood
pressure leads to a decrease of 15% in the risk for DME, A Cochrane review also found that aggressive
blood pressure control could modestly reduce the risk of DR development but not its progression. 33
Therefore, overaggressive blood pressure control could be avoided.34

Recommendation
A four year follow-up from the ACCORD (Action to Control Cardiovascular Risk in Diabetes Trial) Eye
study blood pressure trial demonstrated that there was no significant difference in the progression of
DR with intensive (target systolic BP: <120 mmHg) versus standard BP control (target systolic BP: <140
mmHg) in people with type 2 DM.108

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The evidence behind hyperglycaemia as a risk factor is stronger than that of hypertension and
dyslipidaemia. Therefore, intensive control of hypertension and dyslipidaemia will be most effective
in relation to other complications (e.g. reduction in nephropathy and cardiovascular diseases).

2.3 Dyslipidaemia
The evidence for dyslipidaemia as a risk factor for DME is inconclusive.35 Serum lipids has been found
to have a relationship with DME but not DR36 and lipid levels correlated with DME with central
involvement and hard exudates.37 This suggests hyperlipidaemia may have differing contributions to
the pathogenesis of DR and DME. However, a meta-analysis found that lowering lipid levels was not
associated with lower risk of DME although there was a strong relationship between lipids levels and
DME.38 Raised serum lipids are associated with macular exudates and moderate visual loss; fenofibrate
reduced the need for laser therapy for DME by 31% over five years as shown in the FIELD study.39 This
therapeutic benefit was found to be independent of the baseline lipid levels or the lipid-lowering
effects. Fenofibrate as a peroxisome proliferator-activated receptor alpha agonist can reduce retinal
inflammation and angiogenesis40, and decrease apoptosis, which may account for the lipid
independent effect on DME.41

Recommendation
Lifestyle modification that focuses on weight loss (if indicated). The recommendation of a healthy diet
and increased physical activity may improve the lipid profile. Additionally, optimization of glycemic
control for patients with elevated triglyceride levels (≥150 mg/dL [1.7 mmol/L]) and/or low HDL
cholesterol (<40 mg/dL [1.0 mmol/L] for men, <50 mg/dL [1.3 mmol/L] for women).

2.4 Duration of DM
While all persons with DM have a risk for developing DME, those individuals with higher levels of
glycated hemoglobin (A1C) (>7%) and longer disease duration have the most risk.42 Globally, the
prevalence of DME is substantially higher among individuals with T1DM than those with T2DM.

2.5 DR
DR severity is a major risk factor associated with DME.55 In the WESDR study, DME was present in only
3% of eyes with mild non-proliferative DR, but increased to 38% in eyes with moderate to 71% in eyes
with proliferative DR.52 Recently, findings from a large database study in the UK showed that the risk
of DME increased by more than six times in the presence of any DR, and rose proportionately with
increasing severity of retinopathy.56

2.6 Obesity
Data on the relation between obesity and DME are inconsistent and suggest different effects
depending on the type of diabetes. In people with type 1 diabetes, higher BMI and larger waist-to-hip
ratio are linearly associated with increased risk of DR.42 By contrast, data from cross-sectional studies
of people with type 2 diabetes have shown an inverse relation between obesity and DR or DME.43,44

Recommendation
Evidence-based recommendations including diet, physical activity, and behavioural therapy to support
achieving and maintaining >5% weight loss should be prescribed for people with DM who are
overweight or obese and ready to achieve weight loss. Diets should be individualised with respect to
the person’s preferences and dietary needs.

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2.7 Cataract surgery
People with diabetes have an increased risk of cataract that requires surgery. Even in the absence of
any surgical complications, DME after cataract surgery is more common in patients with diabetes,
especially in those with pre-existing retinopathy.57 A multicentre national diabetic database study
found that DME requiring treatment increased after cataract surgery, with the highest risk in the 3-6
months postoperative period. Other ocular determinants of DME include myopia (short-sightedness),
where there is increasing evidence that myopic eyes with longer axial length, may have a lower risk of
DR and DME .58,59

2.8 Sleep apnoea

One study concluded sleep apnoea is a risk factor, with 54% of patients with DME having sleep
apnoea.47

Recommendation
Research suggests that continuous airway pressure therapy can improve vision in patients with DME.48

2.9 Pregnancy
There have been reports that associate pregnancy with increased risk of DME and DR.60-62 Although
there are fewer studies studying DME in pregnancy compared with those looking at DR, it is likely that
these two ocular co-morbidities have similar aetiologies during pregnancy. Rapid exacerbation and
poor control of hyperglycaemia during pregnancy may lead to increased DR and DME. Furthermore,
pregnancy-induced hypertension, a known complication of pregnancy in many women, may also
increase the risk for DME.63 Although the precise cause is not well known, and various placental
hormones may be implicated60, it is important that pregnant women with diabetes undergo regular
screening to prevent retinopathies such as DME.

Those women with gestational diabetes mellitus (GDM) do not have a greater risk of developing
diabetic retinopathy than the general population with diabetes. Therefore, the population with GDM
does not require routine eye examinations during pregnancy.

3. SCREENING FOR DME

The recommended examination methods include recording the medical history (diabetes control
including blood glucose, blood pressure, and serum lipid) and performing eye screening of the person
with diabetes.

The current gold standard for detecting DR is using a dilated slit-lamp evaluation of the retina and
serial fundus photos. Screening programmes most commonly use non-mydriatic cameras in their
photographic screening campaigns. If a programme does not dilate the pupils of their screened
population, one macular centered field is usually the method of choice. Due to the pupil’s
contraction from the camera flash, usually acquiring only one good quality image is possible. If the
pupils of the screened population are dilated, two fields (one macular centered and one disc
centered) is most commonly used.

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3.1 Retinal Examination
For the retinal examination, the well-trained examiner will perform ophthalmoscopy, or retinal
photography, and will assess the severity of DR in the retinal images.

Initial Examination
 People with type I diabetes should be screened annually for retinopathy five years after the
onset of diabetes.
 People with type 2 diabetes should have initial examination for retinopathy shortly
after the diagnosis, and should repeat the examination at least annually, as per the
severity of the retinopathy.
 In pregnant women with pre-existing type 1 or type 2 diabetes, eye examinations
should occur before conception, soon after, or in the first trimester. These women
should undergo monitoring every trimester, and for one year postpartum as
indicated by the degree of retinopathy.
 The population with gestational DM does not require routine eye examinations
during pregnancy.

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Timing of initial and ongoing eye examinations for people with diabetes (eye health
guide 2015)

13
3.2 Examination Method
The retinal examination usually includes one of the two following:

(1) Direct or indirect ophthalmoscopy or slit-lamp biomicroscopic examination of the

retina; or
(2) Retinal (fundus) photography, including:

o 30º to wide field; or

o Monophotography; or
o Stereophotography; or
o Dilated or undilated photography

Consideration for Low-/Intermediate Resource Settings:

Optimally, a screening exam would include:

o Complete ophthalmic examination with refracted visual acuity;
o Pupil dilation; and
o State-of-the-art retinal imaging

However, in low-/intermediate resource settings, the minimum examination components to

assure appropriate referral should include:
o 1) A screening visual acuity exam; (pupil dilation, if done, should precede vision
testing); and

14
 o 2) A retinal examination adequate for DR classification75

In people with no retinopathy, a one to two year screening interval could suffice. However, a positive
retinopathy diagnosis warrants yearly, or more frequent, screening.

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3.3 When to Refer to Ophthalmologist
As per ICO guidelines of Diabetic Eye care, the minimum guidelines are:

Visual acuity below 6/12 (20/40) or symptomatic vision complaints

If visual acuity or retinal examination cannot be obtained at the screening examination: refer to
ophthalmologist. Other considerations requiring follow-up:

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  Patients with an inadequate retinal assessment, unless it is obvious that there is no DR, or at
most, only mild nonproliferative DR (i.e., microaneurysms only)
 Unexplained visual-acuity loss
 Women with T1 or T2 diabetes should be asked if they are or could be pregnant.
 Inadequate blood glucose control and pregnancy may require further appropriate medical
intervention.

3.4 Re-Examination and Referral Recommendations

Re-examination and Referral Recommendations Based on International Classification of Diabetic Macular

Edema

For High Resource Settings:

Diabetic Macular Edema

Classification Re-examination Referral to Ophthalmologist
Noncentral-involved DME 3 months Referral required
Central-involved DME 1 month Referral required

For Low-/Intermediate Resource Settings:

Diabetic Macular Edema

Classification
Noncentral-involved DME
Central-involved DME
Re-examination or next Referral to Ophthalmologist
screening schedule
3 months Referral not required
(referral recommended if laser
resources available)
1 month Referral required

As all persons with DM are at risk for developing DR and DME, and people who are not experiencing
visual symptoms already may have advanced stages of the conditions, it is important that they
undergo screening.

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4. TREATMENT OF DME

In addition to the management strategies used for its risk factors, the four main therapeutic options
of the DME treatment are:

 Laser photocoagulation
 Intravitreal injections
 Polytherapy of laser photocoagulation+ VEGF or + intravitreal steroid
treatment
 New guidelines indicate laser photocoagulation and close observation of patients with
noncentral-involved DME and mild visual impairment. For those with central-involved DME
and moderate visual impairment, intravitreal therapy has evolved as the treatment of choice.
The traditional treatment goal of preventing blindness in patients with DME developed into
the new goal aiming to restore impaired vision, prevent further vision loss and improve visual
function. Therapies including intraocular injection of steroids and anti-VEGF agents preserve
the retina better than older therapies, and could be useful in patients for whom conventional
therapy is ineffective.
 The future remains promising as well for the development of alternative modes of treatment,

18
 including the inhibition of other angiogenic factors, regenerative therapy, and topical
therapy.
4.1 Laser Photocoagulation
For more than three decades, the standard therapy for visual impairment caused by DME was focal
and/or grid laser photocoagulation. While effective for stabilizing and preserving remaining sight, its
ability to reverse vision loss is poor.

The precise mechanisms for the effectiveness of focal laser treatment may be due to its ability to block
leaking microaneurysms. Histopathological studies have shown that such therapy triggers changes in
the retina and the retinal pigment epithelium (RPE).122,123 This could reduce the blood flow to the
macula caused by improvements in oxygenation after photocoagulation.124 an indirect effect on
macular edema.127,128

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In diffuse DME, the use of laser photocoagulation in monotherapy, is ineffective, compared to
intravitreal anti-VEGF or corticosteroids monotherapy.135 Intravitreal anti-VEGF or corticosteroids
should be the first-line of therapy. While macular grid laser is less harmful than the conventional laser
grid, it is recommended for patients resistant to intravitreal agents. Many practitioners employ a
combined use of macular laser with intravitreal therapies at the commencement of therapy. The
multifactorial pathophysiology of DME and the multiple cellular and biochemical mechanisms involved
provides a rationale for combined therapy. In some cases, combination therapy with anti-VEGF and
macular laser has been associated with a reduction in the number of injections required over the long
term.136,137 Thus, one can assume laser is still important in DME therapy. 138

In focal or multifocal DME, the laser photocoagulation could be the first-line therapy, provided that:

- the microaneurysms are well identified by angiography;

- the few fluorescein leakage points that are detected should be more than 500 μm from
the center of the macula;
- the eye has not been subjected to previous laser treatment that had an ineffective
result.
Over all side effects to this treatment option include foveal burns, central visual field defects, changes
in contrast sensitivity, impaired night vision, retinal fibrosis, choroidal neovascularization and
scarring.130-132 The overall lack of effectiveness has also often been pointed as an important
limitation as well.132-134

4.2 Intravitreal Injections

The introduction intravitreal injections to treat DME has evolved into the preferred strategy since the
sole use of laser photocoagulation. They include:
 Anti-VEGF therapies
 ranibizumab

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  bevacizumab
 aflibercept
 Corticosteroids
 triamcinolone
 dexamethasone
 Vitreous inserts (sustained delivery)
fluocinolone acetonide

Anti-VEGF therapy

VEGF has been shown to be a proinflammatory cytokine. Anti-VEGF drugs have emerged as the gold
standard for the treatment of centeral involved DME. Three anti-VEGF medications which have been
proven in clinical trials to be effective for the treatment DME and are commonly used are ranibizumab,
bevacizumab and aflibercept.

Anti-VEGF medications are delivered into the eye as intravitreal injections under topical anaesthesia.

Intravitreal ranibizumab has been shown in multiple randomized clinical trials to be consistently
superior to laser therapy alone in both preserving vision and improving long-term vision
outcomes.145,146

Bevacizumab is widely used as an “off-label” treatment for retinal diseases due to its substantially
lower cost, although it is only licensed for use in cancer.

Intravitreal aflibercept is associated with the greatest gain in vision, compared to the other two agents,
particularly among patients with worse baseline visual acuity (20/50 and worse). 153,154

Anti-VEGF drugs for the treatment of DME have also been associated with the additional benefit of
reducing DR progression compared with laser.160In n cases with both PDR and DME, monotherapy
has demonstrated positive outcomes and, in some cases, superior overall vision regain over time,
compared to laser or combination therapy.161,162

21
Although anti-VEGF therapy is usually preferred to laser therapy for DME, about 30-40% patients do
not show complete resolution of edema and vision improvement even after multiple injections. In
these patients, additional pathogenic mediator may play a role in addition to VEGF.

Of note, anti-VEGF medications have a more robust effect in angiogenesis (PDR or neovascularisation
of the iris) compared to that in DME. While PDR seems to be a primarily VEGF-dependent disease, DME
is also involves an inflammatory process. With multiple chemokines and cytokines, involved, new
pharmacotherapies are under development targeting these inflammatory mediators.

Recommendation

Intravitreal administration of anti-VEGF therapy generally is considered safe, and ocular complications
are rare.

In summary, laser photocoagulation remains an important therapeutic option for the control of DME
given that new advances in laser technology will allow for more effective, simpler and safer treatments.
Since new intravitreal therapies may be costlier for national health systems, in settings with limited
resources, a cost-benefit analysis is recommended. It is essential to select the most effective, safest
and adequate therapy, while maintaining universal health care coverage. In light of this, laser will likely
maintain an important role in DME.

22
Corticosteroid therapy

Corticosteroids are used as a second line treatment in patients who are nonresponsive to anti-VEGF
injections.

Corticosteroids provide powerful anti-inflammatory and anti-edematous effects by targeting and

decreasing the synthesis of pro-inflammatory mediators involved in DME. 192

23
Corticosteroid agents

Corticosteroids are commercially available for intravitreal use as triamcinolone acetonide,

dexamethasone implant (Ozurdex®), and fluocinolone (Illuvien®).

Triamcinolone acetonide

Triamcinolone acetonide (TA) was the first corticosteroid agent used intravitreally for the treatment
of DME. 195,196

Despite its efficacy in the treatment of DME, TA bares the potential for side effects with a high rate of
cataract formation or progression and IOP elevation (IOP elevation ≥ 10 mmHg in 40-50% of patients).

Dexamethasone implant

Dexamethasone (DEX) implant (Ozurdex®; Allergan Inc., Irvine, CA, USA) is available as a sterile,
preloaded single-use applicator. The implant is inserted into the vitreous cavity with a 22-G needle via
the pars plana. The implant contains 0.7 mg dexamethasone within a biodegradable polymeric matrix,
allowing slow release of the drug.

The efficacy and safety of DEX implant has been shown in two 3-years multicentre, randomised,
masked, sham injection-controlled phase III clinical trials (MEAD study).198 Minimum treatment
intervals between repeated DEX implants were 6 months, and patients received on average 4-5
treatments over the study period. A larger portion of patients treated with DEX implant enjoyed a
significant improvement in BCVA (22.4 vs. 12.0%, p < 0.002), and a greater reduction in central macular
thickness (112 vs. 42 μm, p < 0.001) compared to patients in the sham group. Moreover, DEX implant
is the only drug which was prospectively investigated in a group of vitrectomised eyes with DME: The
CHAMPLAIN study showed an improvement of 6 and 3 letters at 8 and 26 weeks, respectively, after a
single DEX implant. At 8 weeks, 30.4% of patients gained ≥10 letters.

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In a recent multicentre, open-label, 12-month, randomised, parallel-group study, DEX implant met the
a priori criterion for noninferiority to ranibizumab in improvement of BCVA over 12 months.199 Both,
DEX implant and ranibizumab were well tolerated and improved BCVA and anatomic outcomes in
patients with DME. Noninferiority was achieved with an average of 2.85 DEX implant injections and
8.70 ranibizumab injections per patient.

Similarly, the 24-month results of the BEVORDEX study identified no significant difference in the
proportion of eyes with a 10-letter gain in VA between bevacizumab and DEX implant treatment, with
both agents providing good improvements.200 The burden of injections was significantly greater with
bevacizumab (mean 9.1 vs. 2.8).

As treatment frequency may be set at shorter intervals than in the MEAD trial, real life studies are of
great importance in case of DEX implant. Several large-scale studies have been showing the efficacy
with improvement in BCVA and decrease in retinal thickness201-203, even in eyes with DME refractory
to anti-VEGF.202,204-206

The main side effects of DEX implant are cataract development and IOP increase. In the MEAD trial,
27.7% of patients treated with 0.7 mg DEX implant experienced an increase of ≥10 mmHg, in 6.6% IOP
reached ≥35mmHg. While 41.5% needed IOP lowering medications, only 2 patients treated with DEX
implant underwent incisional surgery. Data from real life studies show an increase of IOP in 10-17% of
patients well managed with topical treatment.202,207

Fluocinolone acetonide

Fluocinolone acetonide (FAc) is available for intravitreal use in two forms: with a dose of 0.59 mg as a
nonbioerodable implant (Retisert®; Bausch + Lomb), implanted surgically through a scleral incision in
an operating room, and as a smaller (0.2 mg) nonbioerodable insert (Iluvien®; Alimera, Alpharetta, GA,
USA), which is inserted with a single-use, preloaded 25-gauge injector as an office procedure. Due to
a high rate of IOP rise ≥30 mmHg with need for incisional surgery and 91% of patients undergoing
cataract surgery in 4 years208, Retisert was not approved for the treatment of DME.

Iluvien 0.19 mg FAc has been approved by the FDA for the treatment of chronic DME considered
insufficiently responsive to other available therapies, in patients previously treated with
corticosteroids that did not show a clinically significant increase in IOP.

The current role of steroids in the treatment algorithm of DME

Patient with a history of major cardiovascular events have an increased risk for death and
cardiovascular accidents under intensive anti-VEGF treatment.216 In this patient population,
corticosteroids should be considered as a first line therapy. Also, patients unable or not willing to
undergo monthly anti-VEGF injections should be offered sustained-release corticosteroids. TA is not
recommended due to its higher rate of side effects.

Steroid treatment is preferred for pseudophakic patients; phakic patients should be informed, and
followed up for the possibility of cataract formation or progression.

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4.3 Polytherapy
Treatment with other therapeutic agents (e.g., anti-inflammatory agents, corticosteroids) may yield
improvements in visual outcome. Focal/grid laser photocoagulation, formally the gold standard
treatment, is now reserved for non-center involving DME. It may be combined with anti-VEGF therapy
for a complete response. Combination therapy of steroids and anti-VEGF agents, and switching to
other anti-VEGF agents may be considered.163 In addition, other factors can contribute to the lack or
loss of anti-VEGF treatment response (e.g., pre-existing damage to the photoreceptors or disruption
of the inner retinal layers due to chronicity of macular edema and/or macular ischaemia).

4.4 Surgical Approaches

Even with the availability of multiple therapeutic agents, including intravitreal anti-VEGF agents, focal
laser and, corticosteroids, refractory DME continues to be a challenge to treating doctors including
retina specialists. However, subsets of patients may benefit from a surgical approach to treat their
DME.

The pathogenesis of DME is multifactorial and includes a cascade of complex biochemical processes.
One theory is that the primary insult of hyperglycaemia leads to the development and acceleration of
advanced glycation end products (AGEs). AGEs promote mechanical changes in the vitreous and at the
vitreous-retinal interface. Vitrectomy may help remove the AGEs from the vitreoretinal interface or
remove abnormally adherent vitreous that could induce DME. 217,218

Theoretically, vitrectomy, with or without membrane removal, may help improve DME via multiple
mechanisms. Surgical treatment for DME is reserved for mechanical causes of the edema.

The lack of correlation between anatomic resolution of edema and improved vision remains a major
outstanding question in understanding surgical treatments for DME. In addition to the surgical risks of
vitrectomy, the increased clearance of anti-VEGF and other pharmacological agents in a vitrectomised
eye should be considered.224

Future Trends in DME Management

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With increasing numbers of people with diabetes, comes an increased number of those at risk for
vision loss due to DME. With the availability of intravitreal injections of VEGF and steroids, there is a
definite improvement in the complications, however, diabetic eye diseases are challenging to treat
due to complex ocular physiology and barrier properties.

The need for intravitreal route of administration may prevent patients completing their treatment.
Since frequent injections may be necessary to maintain therapeutic levels, this may lead to
complications such as retinal detachment, endophthalmitis, pseudoendophthalmitis and retinal
haemorrhage.

To overcome this, increasingly clinicians e combination therapies. Several emerging strategies for DME
show promise for optimal drug delivery and treatment, including nanotechnology-based technologies.

While many of these are still under trial, a list of medications under consideration for managing DME
is provided below:

The treatment of DME in previously vitrectomised eyes

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The treatment of DME in previously vitrectomised eyes isconsidered a special case. The half-life of an
anti-VEGF agent in the vitreous of the vitrectomised eyes lasts for only a few hours, so these types of
medications are not indicated for treatment.139 Postoperative macular laser photocoagulation, or
possibly slow-release corticosteroids implants, would likely be more effective. 140,141

5. SYSTEMIC MANAGEMENT OF DME

The main aims of systemic therapy in DME is to prevent or delay the onset and the rate of progression
of the complication. Systemic therapies target modifiable risk factors such as hyperglycaemia,
hypertension, dyslipidaemia.

Glycemic control
 A significant modifiable risk factor for DR, intensive glycemic control offers important and
enduring protection against development and progression of DR and DME. Evidence of
hypertension and dyslipidemia as risk factors is weaker than of hyperglycemia.Therefore,
intensive control of hypertension and dyslipidemia will be most effective in relation to other
complications (e.g. reduction in nephropathy and cardiovascular diseases).

 One element of the standard of treatment for DME is glycemic control. This recommendation
is based primarily on findings from the Diabetes Control and Complications Trial (DCCT) and its
follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) trial. These
studies found that intensive glycemic control lowered the relative risk of the onset of DME by
46% and 58%, respectively.

 The effectiveness of conservative blood sugar control diminishes once complications have
developed, in older people, or those with macrovascular disease.30

 Glitazones use warrants caution in patients with DME. Fluid retention occurs in 5–15% of
patients taking this category of diabetes medications. Its use appears to be a cause for macular
edema, however, cessation of the medication results in rapid resolution of DME. Therefore,
when considering treatment modalities for DME, clinicians should note if the patient uses
glitazones. 21

 People prescribed glitazones demonstrate an increased rate of fluid retention and thus DME.
The latter resolves upon the cessation of glitazone use. Therefore, treatment considerations
should include the edema associated with these medications, especially in those already
diagnosed with peripheral edema.106

 Guidelines recommend an HbA1c target of 6.5–7.5% (48–58 mmol/mol) with few

hypoglycaemic episodes. However, clinicians should set individualised targets based on age,
disease duration (longer than 10 years), disease progression, risk of hypoglycaemic episodes,
and other factors.

Hypertension

 Optimal control of hypertension is an important means of reducing the progression of DR. The
use of an angiotensin-converting enzyme inhibitor or a beta-blocker for blood pressure
control, resulted in a 34% reduction of progression in retinopathy in the UKPDS.107

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  The Action to Control Cardiovascular Risk in Diabetes Trial) ACCORD eye study demonstrated
that in people with type 2 diabetes, aggressive blood pressure control failed to provide better
protection against the progression of DR than standard control.108

Lipid management

 Multiple large studies have shown an association between total cholesterol (TC) and serum
low-density lipoprotein cholesterol (LDL-C) and hard exudates in people with DR. Therefore,
clinicians should evaluate serum TC and lipids, including non-HDL-C and LDL-C, in their patients
with DME.

 Raised serum lipids are associated with macular exudates and moderate visual loss.

 Decreasing lipid levels does not increase risk of worsening of hard exudates nor severity of
DME.

 Fenofibrate is a medication used for hypercholesterolemia that has benefits beyond its lipid
lowering effect. Use of fenofibrate in 2 large independent clinical trials (FIELD and ACCORD)
demonstrated a reduced risk of DR progression.111-112

 Fenofibrate was shown to reduce the need for focal laser therapy for DME in the FIELD study
by 31% over 5 years.114 In the ACCORD trial, fenofibrate, combined with simvastatin, reduced
the need for laser therapy or surgery by 40%. In addition, emerging evidence suggests that
fenofibrate might reduce macular thickness in people with DME.116

 Fenofibrate reduced the need for laser therapy for DME by 31% over five years as shown in
the FIELD study, and the risk of progression of retinopathy by 79%.39 This therapeutic benefit
was found to be independent of the baseline lipid levels or the lipid-lowering effects.

 Fenofibrate treatment should be strongly recommended for DR cases

 Optimization of blood glucose, blood pressure, and possibly blood lipids control remains the
cornerstone to retard the progression of DR and DME.

Additional considerations:

 Through the exacerbation of hypoxia in the retina, anemia promotes the advancement of DME.
Subsequently, growth factors such as VEGF develop as well.[49] Consequently, an independent
risk factor for high-risk PDR and visual impairment, anemia is a significant risk factor for DME.

 Especially in people diagnosed with sight-threatening retinopathy, PDR and central-involved

DME, clinicians are strongly encouraged to assess haematocrit levels.

 People diagnosed with anemia and renal impairment may experience improved visual acuity
from the intravenous administration of erythropoietin.

6. PATIENT COMMUNICATION AND EDUCATION

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Communication Guiding Principles

- Ensure language used is accessible to the person

- Provide information on consequences
- Jointly set person-centered
Informing and Empowering
When discussing treatment, health professionals should review with the patient:

- The costs and benefits of treatment

- What to expect during and after treatment
- The importance of continued eye examinations
- The role the person can play in their own self-management
- Educate person living with diabetes, family member and/or caregivers about the importance
of maintaining near-normal glucose levels, near-normal blood pressure and to control serum
lipid levels, avoid smoking and high-impact straining, anaerobic exercise.
- Encourage lifestyle modification and provide support for ongoing self-management

Supporting regular check-ups

People may better adhere to regular eye examinations if you:

- Inform people with diabetes that eye examination is important even if their vision is not
impaired
- Place reminders on a calendar or medical record
- Acknowledge and discuss a fear of blindness. This is one of the most common fears and one
reason why people go into denial and do not seek treatment

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