120
VOLUME 10 NUMBER 4 • NOVEMBER 2013
REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
Correspondence to: Dr Carl-Heinz Kruse
Department of Opthalmology, University of
KwaZulu-Natal, Durban
e-mail:
S Afr J Diabetes Vasc Dis
2013;
10
: 120–121
What is the ideal drug for the treatment of diabetic
macular oedema?
CARL-HEINZ KRUSE
Introduction
Diabetes causes multiple end-organ damage, primarily due
to microvascular disease. In the eye, retinal damage (diabetic
retinopathy) can broadly be divided into (1) proliferative diabetic
retinopathy (PDR) with characteristic vascular proliferation, gliosis
and eventual retinal detachment, and (2) diabetic macular oedema
(DMO), which leads to eventual destruction of photoreceptors in
the central vision. DMO is the leading cause of permanent blindness
in diabetics.
The pathogenesis of DMO is multifactorial but the major
hallmark is hyper-permeability of the retinal microvasculature,
leading to retinal oedema and accumulation of proteins and lipids.
If left untreated this inexorably leads to loss of vision, typically to
the level of legal blindness.
Various management options are available for treatment of
DMO, including anti-inflammatory drugs, angiogenesis inhibitors,
photocoagulation therapy, systemic disease control, vitreolytic
agents and other novel drugs. The main goal of this review is to
identify the best long-term, vision-preserving treatment option.
Photocoagulation
DMO treatment employs laser energy by one of two methods: focal
laser to coagulate leaking microaneurisms; and milder, diffuse grid
laser to the entire oedematous area to stimulate resorption of the
macular fluid by the retinal pigment epithelium. Laser treatment
of the macula remains the traditional gold standard of treatment
to this day, primarily due to the long track record, effectiveness
in limiting vision loss, cost effectiveness and the durability of the
treatment.
1,2
Despite being the gold standard, photocoagulation is limited
by not being equally effective in all patients. The therapy is also
primarily aimed at preventing future loss of vision, and very
few patients actually gain significant vision (three lines or more)
following grid/focal laser.
3
In fact, 5% of patients may experience
debilitating loss of visual acuity due to the laser treatment itself.
4
Anti-inflammatory agents
Various inflammatory mediators are responsible for the increased
permeability and leakage in DMO, including tumour necrosis
factor (TNF-
α
), interleukins and vascular endothelial growth factors
(VEGF). Corticosteroids are effective in modulating these mediators
and are therefore often effective in treating DMO.
The limitations of steroid treatment for DMO include the inability
to cross the blood–ocular barrier. Steroids therefore have to be
injected or surgically placed into the vitreous cavity to be effective.
This brings with it all the potential complications of intra-ocular
surgery, including endophthalmitis and iatrogenic damage to the
lens and retina.
The most studied and widely used steroid for intravitreal use is
triamcinolone acetonide (Kenalog™). The steroid crystal suspension
is injected through the pars plana into the vitreous humour and is
effective in reducing macular swelling for four weeks. Newer and
longer-lasting preparations include steroids imbedded in a slowly
disintegrating matrix, such as Ozurdex™, an injectable, flexible rod
impregnated with dexamethasone, which dissolves in four to six
months.
5
Iluvien™, an injectable non-erodible insert, approved in
many European countries, slowly releases fluocinolone acetonide
over two to three years.
6
Steroids often have a dramatic effect in resolving DMO, often
being effective even when laser and anti-angiogenic drugs have
failed.
5
The effect is, however, transient and repeated injections/
operations are often required. Furthermore, all steroids can cause
cataract as well as raised intra-ocular pressure (IOP) which can lead
to glaucomatous optic nerve damage.
7
Of the patients who received
Retisert™, a slow-release steroid, 91% had to have cataract surgery
within four years, almost two-thirds had raised IOP and more than
a third had surgery for glaucoma resistant to medical treatment.
8
Newer, lower-dose devices such as Iluvien™ show some promise in
lowering the number of complications.
6
Non-steroidal anti-inflammatory drugs have a milder treatment
effect and fewer side effects but none have been approved for
intra-ocular use in DMO.
Angiogenesis inhibitors
A number of anti-angiogenic drugs have been approved for
treatment of DMO, of which the most studied is ranibizumab
(Lucentis™). This humanised monoclonal antibody fragment
binds and inactivates VEGF in the vitreous humour, reducing the
hyperpermeability of the macular vessels. Avastin™ (bevacizumab)
is also increasingly being used to treat DMO as an inexpensive off-
label indication and does not seem to be inferior to ranibizumab.
9,10
Pegaptanib (Macugen™) seems to be slightly less effective.
10
The advantage of anti-VEGF agents is that they do not cause
cataracts and do not usually raise intra-ocular pressure, unlike
steroids.
11
The treatment effect is often dramatic but also transient,
and no sustained-release options are currently available. Most anti-
VEGF drugs are injected monthly as required, and the average
number of ranibizumab injections needed to control the DMO in
the first year is nine, and four injections in the second.
12
At one year, the anti-VEGF drugs more than doubled the three-
line gain in vision, and decreased the loss of three lines of vision in
