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Current
Diabetes Reviews
ISSN: 1573-3998
Current Diabetes Reviews
Volume 5, Number 1, February 2009
Contents
Diabetic Retinopathy
Guest Editor: Francisco Gómez-Ulla
Editorial Pp. 1-2
[PMID:
19199890 PubMed - indexed for MEDLINE]
Matabolic Control and Diabetic Retinopathy Pp.
3-7
Monica Rodriguez-Fontal, John B. Kerrison,
D. Virgil Alfaro and Eric P. Jablon
[Abstract] [Full text article] [PMID:
19199891 PubMed - indexed for MEDLINE]
Diabetic Retinopathy and Angiogenesis Pp.
8-13
Talia N. Crawford, D. Virgil Alfaro, III,
John B. Kerrison and Eric P. Jablon
[Abstract] [Full text article] [PMID:
19199892 PubMed - indexed for MEDLINE]
Rubosixtaurin and other pkc Inhibitors in Diabetic
Retinopathy and Macular Edema. Review Pp.
14-17
M. Isabel López Gálvez
[Abstract] [Full text article] [PMID:
19199893 PubMed - indexed for MEDLINE]
Intravitreal Triamcinolone in Diabetic Retinopathy
Pp. 18-25
Maximino J. Abraldes, Maribel Fernández
and Francisco Gómez-Ulla
[Abstract] [Full text article] [PMID:
19199894 PubMed - indexed for MEDLINE]
Intravitreal Inserts of Steroids to Treat Diabetic
Macular Edema Pp. 26-32
Javier A. Montero and José
M. Ruiz-Moreno
[Abstract] [Full text article] [PMID:
19199895 PubMed - indexed for MEDLINE]
Pegaptanib Sodium for the Treatment of Proliferative
Diabetic Retinopathy and Diabetic Macular Edema Pp.
33-38
Gian P. Giuliari, David A. Guel and
Victor H. Gonzalez
[Abstract] [Full text article] [PMID:
19199896 PubMed - indexed for MEDLINE]
Intravitreal Bevacizumab for Diabetic Retinopathy
Pp. 39-46
J. Fernando Arevalo and Rafael
A. Garcia-Amaris
[Abstract] [Full text article] [PMID:
19199897 PubMed - indexed for MEDLINE]
Ranibizumab for Diabetic Retinopathy Pp.
47-51
Monica Rodriguez-Fontal, Virgil Alfaro,
John B. Kerrison and Eric P. Jablon
[Abstract] [Full text article] [PMID:
19199898 PubMed - indexed for MEDLINE]
Anti-angiogenic Drugs as an Adjunctive Therapy in
the Surgical Treatment of Diabetic Retinopathy Pp.
52-56
Marta S. Figueroa, Inés Contreras
and Susana Noval
[Abstract] [Full text article] [PMID:
19199899 PubMed - indexed for MEDLINE]
Enzymatic Vitreolysis Pp. 57-62
Fernando Lopez-Lopez, Maria Rodriguez-Blanco,
Francisco Gómez Ulla and Joaquin Marticorena
[Abstract] [Full text article] [PMID:
19199900 PubMed - indexed for MEDLINE]
Transconjunctival Sutureless 23-gauge Vitrectomy for
Diabetic Retinopathy. Review Pp. 63-66
José G. Arumí, Anna Boixadera,
Vicente Martínez-Castillo and Borja Corcóstegui
[Abstract] [Full text article] [PMID:
19199901 PubMed - indexed for MEDLINE]
Abstracts
[Back to top] [PMID:
19199890 PubMed - indexed for MEDLINE]
Editorial: Diabetic Retinopathy
This issue of CDR contains a range of interesting and up-to-date
articles which review the most recent advances in the Treatment
of Diabetic Retinopathy and which are written by highly respected
groups of investigators. Although laser photocoagulation is
considered to be the standard treatment of Diabetic Retinopathy
for both macular edema and for retinal neovascularization,
there have recently been important advances in this field,
in particular with respect to the treatment of both diabetic
macular edema (DME) and retinal neovascularization in Proliferative
Diabetic Retinopathy (PDR), whether it be with intraocular
steroids and new devices of sustained liberation or with anti-angiogenics.
The first article, by Rodriguez-Fontal et al., reviews
the importance of metabolic control and the long-term benefits
of improving glycemic control, which reduces the risk of any
type of retinopathy. Intensive therapy is most effective when
initiated early in the course of diabetes because it has a
beneficial effect on the development and progression of retinopathy.
The article which follows, by Crawford et al., examines
the role of angiogenic factors and the use of anti-VEGF drugs
to block them. Hypoxia is a key regulator of VEGF-induced
ocular neovascularization. Following the induction of VEGF
by hypoxia, angiogenesis can be controlled by angiogenic inducers
and inhibitors. The balance between VEGF and angiogenic inhibitors
may well determine the proliferation of angiogenesis in diabetic
retinopathy and understanding this is crucial in subsequent
therapeutic strategies.
López reviews the role of human protein kinases. Several
compounds have been developed that are specific inhibitors
of protein kinase C beta isoforms. Synthetic inhibitors of
protein kinases include small molecules that can be easily
administered as oral therapeutic compounds. These inhibitors
can rapidly and often specifically alter the activation state
of a target kinase. So far two protein kinase C inhibitors,
Protein Kinase C 412 and Ruboxistaurin, have been tested in
clinical investigations to study the reduction of microvascular
complications in patients with diabetes. Ruboxistaurin has
appeared as a new alternative in the management of ocular
complications of diabetes and it is necessary to determine
whether it is sufficiently efficacious to be used alone or
whether it has to be used in combination with other treatments
in order to prevent visual loss in patients with diabetes.
Two papers examine the treatment of DME by the use of intraocular
steroids. The first, Abraldes et al., makes a comprenhensive
review of the mechanism of action of triamcinolone acetonide,
its pharmacology and its intraocular use both as treatment
for DME refractary to focal photocoagulation and as adjuvant
to panretinal photocoagulation. Special emphasis is placed
on safety and efficacy data. The second written by Montero
and Ruiz-Moreno, looks at intravitreal inserts, steroids,
dexamethasone and fluocinolone. Different multicentric clinical
trials and their results are examined. They conclude that
the advantages of these systems are that they maintain a stable
and sustained concentration of the drug with higher therapeutic
efficacy thus reducing the number of injections. However,
the complications associated with the use of steroids, such
as cataracts and high intraocular pressure, are very common.
The use of the different anti-VEGFs which are used in ophthalmology
is tackled in three different papers. Each one reviews the
main indications, published results and the experiences of
the authors with the medicine used, as well as an efficacy
and safety profile. The mechanism of action for pegaptanib
sodium (Macugen, Pfizer), ranibizumab (Lucentis, Genentech)
and bevacizumab (Avastin, Genentech) involves specific neutralization
of VEGF. These anti-VEGFs are being evaluated in different
studies and partial results, some of which are reviewed in
this issue, have already been published.
In dealing with Pegaptanib sodium both in the treatment of
DME and in the case of PDR, Giuliari et al. conclude
that these new pharmacologic therapies will cause a paradigmatic
shift in the way we treat patients with ocular diabetic complications.
Arevalo and Garcia-Amaris have passed on to us their considerable
personal experience gained from the use of the intravitreal
Bevacizaumb as primary treatment for DME. Their results indicate
a beneficial effect on macular thickness and visual acuity,
independent of the type of macular edema present. They also
write about their experience and positive results after using
intravitreal Bevacizumab in cases of persistent retinal neovascularization
after scatter photocoagulation in PDR. This new treatment
modality could replace or complement focal/grid laser photocoagulation
in the future. Furthermore, focal/grid laser photocoagulation
could be used to consolidate the results obtained from one
intravitreal bevacizumab injection and decrease the need for
reinjections. Finally, Rodríguez-Fontal et al.
review the pharmacokinetics and mechanism of action of Ranibizumab
and the first clinical trails carried out to treat DME.
In spite of this data, the responses to these treatments as
described in different published articles have been varied
and the benefits have often been transient. As a result, repeated
injections are often necessary. The inability of anti-VEGF
agents to completely inhibit DME may reflect the fact that
their pathogenesis is a complex process involving multiple
pathways which induce angiogenesis. For example eritropoyetine
can be a potent ischemia-induced angiogenic factor that acts
independently of VEGF during retinal angiogenesis in PDR.
On the other hand, carbonic anhydrase works by increasing
permeability in a way which is similar to that of VEGF, but
independent of VEGF.
The use of anti-angiogenic drugs as an adjunctive therapy
in the surgical treatment of diabetic retinopathy is reviewed
by Figueroa et al. Although there are no prospective
studies using important series of patients, the combination
of intravitreal anti-VEGF therapy and vitreoretinal surgery
in PDR has simplified surgical technique and improved surgical
results. In this paper, the main indications for the use of
anti-VEGF agents are reviewed with respect to: prior to and
at the end of surgical procedure; as therapy for postoperative
vitreous hemorrhage; and also as therapy for iris neovascularization
and neovascular glaucoma.
In a paper of considerable relevance, López-López
et al. look at enzimatic vitreolysis. They review
different clinical trials which are currently underway and
which are using microplasmin, as well as plasmin activated
by certain substances like urokinase. They also review the
main indications for their use, as in the case of DME or vitreous-macular
traction syndrome.
Finally, when either laser photocoagulation or the new treatments
mentioned here fail and it is necessary to resort to surgical
intervention, García-Arumi et al. bring us
up to date on modern surgical techniques using transconjunctival
sutureless 23-gauge vitrectomy. Main indications, technical
difficulties and possible complications are reviewed.
I hope that these different articles, as well as the experience
of each author will help the reader not only to clarify and
improve his understanding of the new treatments for Diabetic
Retinopathy, but also to catch a glimpse of what may well
be the future of this disorder.
Prof. Francisco Gómez-Ulla, MD, PhD.
University of Santiago de Compostela
Instituto Tecnológico de Oftalmología (ITO)
Avda de las Burgas, 2. 15705
Santiago de Compostela
Spain
E-mail: gomezulla@itogalicia.es
[Back to top] [PMID:
19199891 PubMed - indexed for MEDLINE]
Matabolic Control and Diabetic Retinopathy
Monica Rodriguez-Fontal, John B. Kerrison,
D. Virgil Alfaro and Eric P. Jablon
[Full text article]
The Early Treatment Diabetic Retinopathy Study (ETDRS)
identified important risk factors for progression to high
risk proliferative diabetic retinopathy (PDR) including retinopathy
severity, decreased visual acuity, and high levels of hemoglobin
A1C (HbA1c). Additional risk factors for progression to PDR
are decreased hematocrit and increased serum lipids.
The long-term benefit of improving glycemic control was evaluated
by three large studies: the Diabetes Control and Complications
Trial (DCCT), the Stockholm Interventional Study, and the
UK prospective study. Several small studies, notably the Kuwamoto
study, also evaluated the relationship between the glycemic
control and diabetic retinopathy. Intensive glycemic control
reduces the risk of any retinopathy by approximately 27%.
Intensive therapy is most effective when initiated early in
the course of the diabetes, demonstrating a beneficial effect
over the course and progression of retinopathy.
The long term benefits of the intensive glycemic control greatly
outweigh the risk of “early worsening.” Lowering
elevated serum lipid levels has been shown to decrease the
risk of cardiovascular morbidity. The ETDRS data suggest that
lipid lowering may also decrease the risk of hard exudate
formation and associated vision loss in patients with diabetic
retinopathy. Preservation of vision may be an additional motivating
factor for lowering serum lipid levels in persons with diabetic
retinopathy and elevated serum lipid levels.
[Back to top] [PMID:
19199892 PubMed - indexed for MEDLINE]
Diabetic Retinopathy and Angiogenesis
Talia N. Crawford, D. Virgil Alfaro, III,
John B. Kerrison and Eric P. Jablon
[Full text article]
Diabetic retinopathy, a secondary microvascular complication
of diabetes mellitus is the leading cause of blindness in
the Unites States amongst individuals age 20 to 64. Two major
retinal problems cause most of the diabetes-related vision
loss: diabetic macular edema and complications from abnormal
retinal blood vessel growth, angiogenesis. Secondary to angiogenesis,
increased retinal blood flow is of pathogenic importance in
the progression of diabetic retinopathy. Understanding the
role of hyperglycemia seems to be the most critical factor
in regulating retinal blood flow, as increased levels of blood
glucose are thought to have a structural and physiological
effect on retinal capillaries causing them to be both functionally
and anatomically incompetent. High blood glucose induces hypoxia
in retinal tissues, thus leading to the production of VEGF-A
(vascular endothelial growth factor protein). Hypoxia is a
key regulator of VEGF-induced ocular neovascularization. Secondary
to the induction of VEGF by hypoxia, angiogenesis can be controlled
by angiogenic inducers and inhibitors. The balance between
VEGF and angiogenic inhibitors may determine the proliferation
of angiogenesis in diabetic retinopathy. Since VEGF-A is a
powerful angiogenic inducer, utilizing anti-VEGF treatments
has proved to be a successful protocol in the treatment of
proliferative diabetic retinopathy.
[Back to top] [PMID:
19199893 PubMed - indexed for MEDLINE]
Rubosixtaurin and other
pkc Inhibitors in Diabetic Retinopathy and Macular Edema.
Review
M. Isabel López Gálvez
[Full text article]
Diabetic retinopathy (DR) and diabetic macular edema
(DME) are frequent long term ocular complications in diabetic
patients and may produce serious effects on visual acuity
(VA), sometimes leading to blindness. The high and increasing
prevalence of diabetes worldwide suggests that both complications
will continue to be the main cause of vision loss and associated
impairment for a long time [1]. The development and progression
of DR is related to blood glucose concentration and is slowed
by intensive glycemic control [2].
[Back to top] [PMID:
19199894 PubMed - indexed for MEDLINE]
Intravitreal Triamcinolone in Diabetic Retinopathy
Maximino J. Abraldes, Maribel Fernández
and Francisco Gómez-Ulla
[Full text article]
Diabetic macular edema is an important cause of visual
loss in the developed world and may frequently lead to irreversible
changes in visual acuity. The Early Treatment Diabetic Retinopathy
Study showed a significant benefit in using focal laser photocoagulation
for the treatment of macular edema, more specifically defined
as clinically significant macular edema. However, some cases
of diabetic macular edema are refractory to laser therapy
and do not have a good prognosis with such treatment. Triamcinolone
acetonide is glucocoticosteroid with antiangiogenic and antiedematous
properties. Recently, some promising results, respect to the
increases of visual acuity and decreases in foveal thickness,
have been shown in different studies for the treatment of
refractory diabetic macular edema with intravitreal triamcinolone
acetonide.
[Back to top] [PMID:
19199895 PubMed - indexed for MEDLINE]
Intravitreal Inserts of Steroids to Treat Diabetic
Macular Edema
Javier A. Montero and José
M. Ruiz-Moreno
[Full text article]
Diabetic retinopathy is the leading cause of blindness
in developed countries. Diabetic macular edema (DME) is the
most frequent cause of vision loss in patients with type 2
diabetes.
Steroids may reduce the concentration of inflammatory cytokines
and growth factors, and have effect on increased vascular
permeability. Topical steroids does not reach intraocular
therapeutic concentrations and periocular injection requires
frequent injections at the risk of complications. Systemic
administration of steroids may be useful, but high doses are
required and are associated with severe systemic side effects.
Intravitreal injection of steroids provides a powerful therapeutic
effect, but it is associated with frequent secondary cataracts
and increased IOP. The need for repeated injections may increase
the risks associated with the injection procedure.
Preliminary studies have proved the possibility of implanting
sustained release inserts in the vitreous body, allowing for
therapeutic levels of steroids in the vitreous cavity and
retina for more than six months. The advantages of these systems
are to keep a stable and sustained concentration of the drug
with higher therapeutic efficacy thus reducing the number
of injections. However, the complications associated with
the use of steroids such as cataracts and high IOP are very
common.
[Back to top] [PMID:
19199896 PubMed - indexed for MEDLINE]
Pegaptanib Sodium for the Treatment of Proliferative
Diabetic Retinopathy and Diabetic Macular Edema
Gian P. Giuliari, David A. Guel and
Victor H. Gonzalez
[Full text article]
Diabetes mellitus is a growing health concern world-wide.
Patients with this disease present with a variety of health
conditions, including a number of sight-threatening ocular
pathologies. Proliferative diabetic retinopathy (PDR) and
diabetic macula edema (DME) are common diseases that cause
substantial vision impairment in diabetic patients. There
has been a strong focus on studying the epidemiology and treatment
of these diseases. The recent discovery of vascular endothelial
growth factor (VEGF) and its role in the development of proliferative
disease, has led to a movement towards treating PDR and DME
with anti-angiogenic medications in conjunction with the standard
of care.
In this review we present a summary of the origination and
progression of PDR and DME. This will be followed by a review
of clinical data surrounding new anti-angiogenic treatment
modalities.
[Back to top] [PMID:
19199897 PubMed - indexed for MEDLINE]
Intravitreal Bevacizumab for Diabetic Retinopathy
J. Fernando Arevalo and Rafael
A. Garcia-Amaris
[Full text article]
Diabetic retinopathy (DR) remains the major threat
to sight in the working age population. Diabetic macular edema
(DME) is a manifestation of DR that produces loss of central
vision. Macular edema within 1 disk diameter of the fovea
is present in 9% of the diabetic population. Proliferative
diabetic retinopathy (PDR) is a major cause of visual loss
in diabetic patients. In PDR, the growth of new vessels from
the retina or optic nerve, is thought to occur as a result
of vascular endothelial growth factor (VEGF) release into
the vitreous cavity as a response to ischemia. Furthermore,
VEGF increases vessel permeability leading to deposition of
proteins in the interstitium that facilitate the process of
angiogenesis and macular edema. This review demonstrates multiple
benefits of intravitreal bevacizumab on DR including DME and
PDR. The results indicate that intravitreal bevacizumab injections
may have a beneficial effect on macular thickness and visual
acuity (VA), independent of the type of macular edema that
is present. Therefore, in the future this new treatment modality
could replace or complement focal/grid laser photocoagulation
in DME. In addition, in PDR, this new option could be an adjuvant
agent to PRP so that more selective therapy may be applied.
[Back to top] [PMID:
19199898 PubMed - indexed for MEDLINE]
Ranibizumab for Diabetic Retinopathy
Monica Rodriguez-Fontal, Virgil Alfaro,
John B. Kerrison and Eric P. Jablon
[Full text article]
Ranibizumab (Lucentis®)
is a Fab-Antibody with high affinity for VEGF, and is being
designed to bind to all VEGF isoforms. This quality makes
it a powerful drug for VEGF inhibition. Diseases of retinal
and choroidal blood vessels are the most prevalent causes
of moderate and severe vision loss in developed countries.
Vascular endothelial growth factor plays a critical role in
the pathogenesis of many of these diseases.
Results of the pilot studies showed that intraocular injections
of ranibizumab (Lucentis®)
decrease the mean retinal thickness and improve the BCVA in
all the subjects. Proliferative diabetic retinopathy, currently
treated with destructive laser photocoagulation, represents
another potential target for anti-VEGF therapy. The early
experience in animal models with proliferative retinopathy
and neovascular glaucoma shows that posterior and anterior
neovascularizations are very sensitive to anti-VEGF therapy.
The outcome of two phase III clinical trials will increase
our knowledge of the role of Lucentis®
in the treatment of DME.
[Back to top] [PMID:
19199899 PubMed - indexed for MEDLINE]
Anti-angiogenic Drugs as an Adjunctive Therapy in
the Surgical Treatment of Diabetic Retinopathy
Marta S. Figueroa, Inés Contreras
and Susana Noval
[Full text article]
Anti-VEGF drugs may be employed in the surgical treatment
of diabetic retinopathy:
1. Prior to surgery. The intravitreal injection of anti-VEGF
drugs leads to a significant reduction of neovascularization,
with a reduction in the adherence of the fibrovascular complex
to the retina. This simplifies viscodelamination and reduces
intraoperative bleeding during delamination and segmentation.
To minimize the risk of tractional retinal detachment due
to the contraction of fibrovascular tissue, vitrectomy must
be performed within one week after the injection.
2. To decrease the risk of postoperative bleeding. Recurrent
vitreous hemorrhages after vitrectomy are often due to small
bleeding from persistent neovascularization. The injection
of anti-VEGF drugs at the end of vitrectomy could prevent
bleeding from these vessels by blocking the pro-inflammatory
stimulus of the surgical procedure.
3. To treat postoperative vitreous hemorrhage. The intravitreal
injection of anti-VEGF drugs in patients with postoperative
bleeding leads to resolution of the hemorrhage.
4. To treat rubeosis iridis. In eyes with complete panretinal
photocoagulation, the combination of cryotherapy and intravitreal
anti-VEGF injection in the same surgical procedure produces
a disappearance of iris neovascularization together with a
long term effect with no recurrences. In neovascular glaucoma,
anti-VEGF drugs can also facilitate filtrating surgery.
[Back to top] [PMID:
19199900 PubMed - indexed for MEDLINE]
Enzymatic Vitreolysis
Fernando Lopez-Lopez, Maria Rodriguez-Blanco,
Francisco Gómez Ulla and Joaquin Marticorena
[Full text article]
In the absence of posterior vitreous detachment, vitreous
cortex is adhered to the internal limiting lamina of the inner
retina. This junction between the vitreous and the retina
is thought to participate in the pathophysiology of diverse
retinal diseases, including proliferative diabetic retinopathy
and diabetic macular edema. Vitrectomy has been associated
with decrease of macular edema and improvement of visual acuity
in eyes of diabetic patients. Thus, many pharmacologic agents
have been studied with the aim of inducing a posterior vitreous
detachment in order to facilitate the surgical procedure and
reduce complications of vitrectomy. More recently, different
agents such as plasmin and microplasmin have shown to be able
to induce a posterior vitreous detachment given as a single
intravitreal injection. The aim of this article is to give
a scope about the pharmacologic vitreolysis and posterior
vitreous detachment studies and describe some ongoing clinical
trials that will determine the efficacy and safety of these
novel therapies for diabetic retinopathy.
[Back to top] [PMID:
19199901 PubMed - indexed for MEDLINE]
Transconjunctival Sutureless 23-gauge Vitrectomy for
Diabetic Retinopathy. Review
José G. Arumí, Anna Boixadera,
Vicente Martínez-Castillo and Borja Corcóstegui
[Full text article]
This paper reviews the current experience and trends
in 23-gauge transconjunctival sutureless vitrectomy for diabetic
retinopathy in those patients that need a surgical intervention
for either vitreous hemorrhage, fibrovascular proliferation
with traction retinal detachment affecting or threatening
the macula, traction-rhegmatogenous retinal detachment, or
refractory macular edema with taut posterior hyaloid. Since
the instruments in 23-gauge vitrectomy are less flexible and
perform in a more similar way to 20-gauge instruments, the
vitrectomy is more thorough and for more complex manoeuvres
can be done. The 23-gauge transconjuntival sutureless vitrectomy
avoids some of the shortcomings of the 25-gauge systems.
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