New & Emerging

Treatment Of
Diabetic Retinopathy
Presented by:
Pauline Teo Siew Chin

7th January, 2009

 Outline
 Introduction
 Pathogenesis
 Symptoms
 Treatment
 laser treatment
 surgery
 emerging pharmacological treatment
 Summary
 References
 Diabetes Mellitus
 Is a metabolic abnormality in which the blood
sugar concentration is persistently elevated1
 A recent national health survey estimated that
about 1.9 million Malaysians suffer from DM1
 If uncontrolled over time, will lead to
pathological changes which might involve
retina, brain & kidney2
 Retina & Diabetic
Retinopathy3
 Retina: the seeing tissue of the eye
 2 parts: (i) peripheral retina
(ii) macula (central part)
 Diabetic Retinopathy (DR) : blood
vessels of the retina become abnormal
& affect eyesight
 Diabetic Retinopathy4
 Diabetic eye disease is one of the
commonest causes of visual loss in adults
of working age in Malaysia.
 Sight-threatening diabetic retinopathy
causes no symptoms in its early stages,
when it is most amenable to treatment.
 About 30% of the diagnosed diabetic
population has retinopathy & each year
1% develop sight-threatening retinopathy.
 Type of Diabetic
Retinopathy3,5
(i) Background DR or Non-Proliferative DR
- retinal blood vessels develop tiny leaks & cause fluid or blood
to seep into retina retina becomes wet & swollen diminution
of vision
(ii) Proliferative DR
- retina depends on blood vessels for nutritions
- closure of retinal blood vessels foster the growth of
abnormal new blood vessels fragile can cause bleeding &
traction  retinal detachment & total loss of vision
 Pathogenesis 6

Hyperglycemia

1. Diacylglycerol
2. Polyol Pathway Sorbitol
3. Superoxide
4. Glycation
AGE
VEGF
Inflammation Microvascular
PKC β activation Damage
AGE: Advanced glycation end-products
VEGF: Vascular endothelial growth factor
 Diabetic Retinopathy2,4,7
 Duration of diabetes is the
most important factor
determining the prevalence
& severity of retinopathy

 Prevalence of DR (Malaysia)
(i) type I DM : 9.9% (5 years), ↑ to 35.8% (10 years)
(ii) type II DM: 10.0% (5 years), ↑ to 42.9% (10 years)
 Other risk factors: age, type of diabetes, hypertension,
pregnancy, hyperlipidemia, diabetic nephropathy
 Symptoms
 Symptoms: gradual progressive diminution of vision,
sudden loss of vision, difficulty in reading, seeing
floaters in front of the eye5

Vision with diabetic retinopathy

 Diabetic Retinopathy
Treatment4,8
 The treatment of DR is based on disease stage
 Initial stages: Only require periodic follow-up
 Severe: laser treatment, surgery
 Control of systemic factors
 Glycemic control: preprandial=5.0-7.2 mmol/L
postprandial =<10.0 mmol/L
HbA1c =<7%
Tight BP control: 130/85 mmHg
 Lipid control
 Potential & emerging pharmacological treatment
 Laser Treatment 3,5

 Helpful in limiting the damage caused by DR

 laser beam is a high energy light that turns to
heat when it is focused on the parts of the
retina to be treated
 NPDR laser heat either seals or reduces
the leakage of fluid from the blood vessels &
allows the macula to dry
 PDR laser destroys the diseased portions
of the retina to stop the growth of new blood
vessels
Laser Treatment
Laser Treatment
Side effects3,5
• Decrease in the peripheral
field of vision
• Decrease in central vision
• Decrease in color vision
• Difficulty in seeing at night
 Vitrectomy
(Surgery)3,8
 Is done in cases of severe complications
of PDR (eg: nonclearing haemorrhage,
tractional retinal detachment)
 Blood filled vitreous is removed &
replaced with clear fluid, using very
delicated instruments with the help of a
microscope
 An Era of New Therapy
Evaluation
 Extensive research initiatives have greatly
expanded of the underlying mechanisms
of diabetic retinopathy
 New molecular targets for novel
therapeutic agents have been developed
 Potential & Emerging
Pharmacological
Treatment
 Systemic Agent
 Protein Kinase C (PKC) Inhibitors
 Aldose Reductase Inhibitors
 Intravitreous Agent
 Corticosteroids
 Vascular Endothelial Growth Factor
Inhibitor (VEGF inhibitors )
 Drug Targets6
Hyperglycemia
Aldose reductase
inhibitors
1. Diacylglycerol
2. Polyol Pathway Sorbitol
3. Superoxide
4. Glycation
AGE
VEGF VEGF inhibitors
Inflammation Microvascular
PKC β activation Damage
PKC β inhibitors
 Protein Kinase C β
1. Diacylglycerol
Hyperglycemia 2. Polyol Pathway
3. Superoxide
4. Glycation

PKC β activation

neovascularization endothelial vascular

hyperplasia permeability

Microvascular
Damage
 Ruboxistaurin (ArxxantTM )
8,9,11

 Is an investigational PKC β inhibitor

 For treating moderate to severe NPDR
 It works by specifically inhibiting PKC β
 Eli Lilly & company has submitted a new
drug application (NDA) to seek approval
from the U.S. FDA for treatment of DR in
Feb. 2006
 Ruboxistaurin
(ArxxantTM )
 Has been shown in diabetic animal models
to prevent or reverse early blood flow
abnormalities seen in retinopathy,
neuropathy & nephropathy
 First oral pharmacologic agent shown to
reduce visual loss in diabetic patients over
an extended period
 Ruboxistaurin
(ArxxantTM )
 PKC β Inhibitor Diabetic Retinopathy Study 2:
 reduces the occurrence of sustained
moderate visual loss by 40% in patients with
moderately severe to very severe NPDR
 Effective Oral Dose: 32 mg/day
 Adverse effects: coronary artery disease,
diarrhea & asthma
 Aldose Reductase
in the Polyol Pathway6
 Aldose Reductase
Inhibitors6,8,11
Mechanism
 Inhibit aldose reductase
 Stop conversion of glucose to sorbitol
 Decreases AGE
 Decreases PKC beta
 Decreases oxygen free radicals
Aldose Reductase Inhibitors
 Agents with published clinical trials studied
within last 5 years
 Epalrestat, Fidarestat, Ranirestat
 Clinical Efficacy
 Better than placebo for neuropathy
 Clinical trials of ARIs for treatment of
DR  disappointing
Intravitreal Injection

A way to deliver drugs to the posterior portion of the eye,

in close proximity to the retina8
 Intravitreal
Corticosteroids
in Clinical Trials6
Agent Description
Anecortave acetate Steroid derivative
Dexamethasone Corticosteroids implant

Fluocinolone Corticosteroids implant

acetonide
Triamcinolone Crystalline cortisone injection
 Intravitreal Injection of
Triamcinolone Acetonide8,10,12
 Slow-release steroid
 Mechanism:
 suppresses inflammation
 reduces extravasion from leaking blood vessels
 inhibits fibrovascular proliferation
 inhibits VEGF gene expression
 A readily available pharmacologic agent (Kenalog®)
 Inexpensive
 Intravitreal Injection of
Triamcinolone Acetonide
 Most convincing evidence for effect in treating DMO
 RCT by Gillies et al. in 2006
 n = 69 eyes
 Dose of IVTA = 4mg every 6 mths
 Results: 56% treated with IVTA gained 5 or
more letters in best-corrected VA compared with
26% treated with placebo
 “Off–label” use of Kenalog® in treating DMO
 Most common side effects:
 steroid-induced glaucoma
 steroid-induced cataract
 Vascular Endothelial Growth
Factor8
 Is produced in response to hypoxia from
capillary loss and/or microaneurysm
formation
 A key mediator of angiogenesis and
blood-retina barrier breakdown in the
ischemic retina
 Inhibition  prevention of PDR
 Intravitreal VEGF
Inhibitors
in Clinical Trials
Agent Description
Bevacizumab Monoclonal antibody injection
Pegaptanib Binds to VEGF & antagonizes
Ranibizumab Monoclonal antibody injection
 VEGF Inhibitors6,8,12
 Bevacizumab (AvastinTM )
 US FDA approved for metastatic colorectal
cancer in Feb 26,2004
 Pegaptanib sodium (Macugen®)
 US FDA approved for neovascular age-
related macular degeneration (AMD) in Dec 17,
2004
 Ranibizumab (Lucentis®)
 US FDA approved for all form of wet AMD
in July 2006
 Bevacizumab
(AvastinTM )
 Bevacizumab (AvastinTM ) is a full-length,
humanized, murine monoclonal antibody
directed against all the biologically active
forms of VEGF
 AvastinTM is the first anti-VEGF drug to be

approved by the FDA, was developed as an

intravenous therapy for end stage colorectal

cancer
 Bevacizumab (AvastinTM )
 To date, AvastinTM is well known for off-
label use of intravitreous injection in
treating AMD
 Study dosage: 6.2 mcg – 1.25mg
Pegaptanib (Macugen®)
 Pegaptanib is a modified RNA aptamer

that binds VEGF

 FDA approved in all form of wet AMD
in 2004
 Not FDA approved for NPDR, PDR
and DMO
 Effective Dose: 0.3mg every 6 weeks
 Significant side effect: endophthalmitis
 Ranibizumab
(Lucentis )
®
 Ranibizumab is a recombinant, humanized
monoclonal anti-VEGF antibody fragment
 Lucentis® is designed to block new blood
vessel growth and leakiness, which lead to
wet AMD disease progression and vision
loss
 FDA approved in all form of wet AMD at July
2006
 Study Dosage: 0.3mg, 0.5mg
 Significant side effect: ocular inflammation
 Other Potential
Treatment6,8,11
 NSAIDS – Nepafenac
 normally used as an eye drop following
cataract surgery
 has been shown to help in reducing
retinal microvascular problems and other
eye abnormalities in diabetic rats
 Other Potential
Treatment6,8,11
 Low dose Aspirin might help to reduce the

risk of vision loss from diabetic retinopathy

 Research is continuing to determine
minimal dosage that might offer a protective
effect against eye damage
 Other Potential
Treatment6,8,11
 ACEIs/ARBs: Lisinopril, Candesartan
 Growth hormone inhibitors: Octreotide
 COX-2 inhibitors: Celecoxib
 Advanced glycation end-products
inhibitors:
Aminoguanidine
 Summary
 The first line of treatment for diabetes and its
complication is managing the diabetes
 Tight control of blood glucose & BP has been
shown to help prevent & slow progression of
diabetic eye disease
 Primary goal of therapy for DR is to improve or
preserve vision
 Summary
 Laser treatment can be used to treat some forms of
diabetic retinopathy
 If the bleeding is severe, vitrectomy surgery should be
perform
 Recent studies show promising results
 PKC β inhibitors
 aldose reductase inhibitors
 intravitreal corticosteroids
 intravitreal VEGF inhibitors
 References
1 Retina and Vitreous: Diabetic Retinopathy. Retrieved December 22,
2008 from http://www.eyesondiabetes.org.au/
2 Viswanath K & McGavin DDM 2003. Diabetic Retinopathy: Clinical
Findings & Management. Community Eye Health Vol 16:46:21-24.
3 Visitech: Diabetic Retinopathy Treatment. Retrieved December 24,
2008 from www.visitech.org/diabetic-retinopathy-treatment.html
4 Malaysia Diabetic Retinopathy Guideline. Ministry of Health Malaysia &
Academy of Medicine October 1997.
5 Eyeway.org: Diabetic Retinopathy-A threat to your vision. Retrieved
December 24, 2008 from http://www.eyeway.org/inform/retinopathy.htm
6 Amphornphruet A 2007. Medical Treatment in Diabetic Retinopathy.
7 Goh PP 2008. Status of Diabetic Retinopathy Among Diabetics Registered
to the Diabetic Eye Registry, National Eye Database, 2007. Medical
Journal Malaysia Vol 63:Supplement C.
 References
8 Yam JCS & Kwok AKH 2007. Update on the treatment of diabetic
retinopathy. Hong Kong Medical Journal Vol 13:1:46-59.
9 Emerging Drug List: Ruboxistauran Mesylate Hydrate. Canadian
Agency for Drugs & Technologies in Health No.73 June 2006.
10 Michael S 2004. Intravitreal Injection of Triamcinolone: An emerging
treatment for diabetic macular edema. Diabetes Care Vol 27:7:1794-
1797.
11 Mehr D 2006. Diabetic Retinopathy Handouts: Current Concepts in
the Diagnosis & Treatment of Diabetic Retinopathy
12 Lacy CF, Armstrong LL, Goldman MP, Lance LL, 2006. Drug
Information Handbook International (14th edition). Lexi-Comp Inc.