Retinopatia diabetica : quando e come trattarla

Università degli Studi di Palermo

Scuola di Medicina e Chirurgia Dipartimento di Biomedicina Sperimentale

e Neuroscienze Cliniche

Sezione di Oftalmologia

Responsabile: Prof. Salvatore Cillino

Salvatore Cillino

Simona Di Naro

Valentina Sunseri

Anna Mangione

Diabetic Retinopathy

Epidemiology

• The total number of people with diabetes is projected

to rise from 285 million in 2010 to 439 million in 2030.

• Diabetic retinopathy is responsible for 1.8 million of

the 37 million cases of blindness throughout the

world.

• Diabetic retinopathy (DR) is the leading cause of

blindness in people of working age in industrialized

countries.

• The best predictor of diabetic retinopathy is the duration

of the disease

• After 20 years of diabetes, nearly 99% of patients with

type 1 diabetes and 60% with type 2 have some degree

on diabetic retinopathy

• 33% of patients with diabetes have signs of diabetic

retinopathy

• People with diabetes are 25 times more likely to become

blind than the general population.

Diabetic Retinopathy

Epidemiology

Ophthalmology Myron Yanoff MD and Jay S. Duker

Basic and Clinical Science Course, Section 12: Retina and

Vitreous AAO

http://www.aao.org/eyecare/news/upload/Eye-Health-Fact-Sheet.pdf -

• DR was a cause of 4,8% of global blindness in 2002,

3,9% in 2004 and 1% in 2010

• The percentage of adults with diagnosed diabetes, who

reported visual impairment, declined significantly,

from 23.7% in 1997 to 16.7% in 2010

Diabetic Retinopathy

Epidemiology

Relationship between oxidative stress and DR

Polyol pathway AGE RAGE PKC

DR

Suk-Yee Li,Zhong Jie Fu, and Amy C. Y. Lo. Hypoxia-Induced Oxidative Stress in Ischemic Retinopathy.

Oxidative Medicine and Cellular Longevity Volume 2012, doi:10.1155/2012/426769

Hexosamine

I/R

ROS/RNS

Lipid

peroxidation PARP JNK p38 MAPK NFkB Mitochondrial

dysfunction

Inflammatory Biomarkers in Diabetic Retinopathy

Cotton – wool

spot

Neovascularization

Ischemia

Neovascular

glaucoma

Microvascular Occlusion

Fibrovascular

bands

Vitreous

hemorrhage

Increased VEFG

Tractional retinal

detachment Retina in systemic disease : a color manual of

ophthalmoscopy / Homayoun Tabandeh, Morton F.

Goldberg 2009

Infarction

Edema Retinal

hemorrhage Hard exudates

Microvascular

Leakage

Edema Maculare Diabetico

Diabetic Macular Edema (DME):

Consiste nell’accumulo di fluido

nello spessore della retina a

livello della macula per una

eccessiva essudazione,

leakage, di fluidi e di

macromolecole lipidiche dai

vasi capillari retinici

DME

Microaneurysm Retinal capillary

Fovea

Edema

Retina

RPE layer

Choroid

Hard exudate

Patogenesi del DME

Bhagat N et al. Surv Ophthalmol 2009;54:1–32

AII, angiotensina II; AGE, prodotti finali glicazione avanzata; BRB, barriera

emato-retinica; DAG, diacilglicerolo; ET, endotelina; LPO, lipossigenasi;

MMP, matrice metallo-proteinasi; NO, ossido nitrico; PKC, proteina chinasi

C; PPVP, posterior precortical vitreous pocket; RAS, sistema renina

angiotensina

Ruolo di fattori genetici? Iperglicemia

Edema

maculare

AGEs

ET

VEGF Ipossia IL-6 Destabilizzazione del vitreo

Anomalie nel collagen cross-linking

MMP attività

PPVP

DAG

PKC

Vasocostrizione

Istamine

Recettori ET sui

periciti Danno ossidativo

LPO, NO, NADH/NAD+

Enzimi antiossidanti

RAS

attivazione

Tensione del vitro maculare

Accumulo di

citocheratina e glial

fibrillary acidic

protein

Fosforilazione delle

giunzione proteiche

strette

Disorganizzazione della

BRB

AII

Diabetic macular edema

• Diabetic macular edema can be present at any

stage of the disease, but is more common in

patients with proliferative diabetic retinopathy

• Diabetic macular edema is the leading cause of

legal blindness in diabetics.

DR diagnosis

• ETDRS acuity

• Midriatic examination (retinography)

• OCT – Quantification and qualification of the edema

– Evaluation of the vitreous - retinal interface

DR diagnosis

• FAG – Evaluation of the retinal circulation and abnormalities

(IRMA, neovascularization, …)

– Recognition of retinal ischemia areas

– Evaluation of macular edema

DR diagnosis

• Microperimetry (SLO)

• Multifocal ERG

DR diagnosis

• Ecography

Risk factors

Changeables Low metabolic

control

Hyperlipemia

Obesity

Smoking

High blood

pressure

Not changeables Age

Familiarity

Race

Duration of

diabetes

Mild nonproliferative diabetic

retinopathy

Microaneurysms

Moderate Nonproliferative

Diabetic Retinopathy (NPDR)

Hard exudates

Flamed shaped

hemorrhage

Microaneurysm

DCCT (Diabetic Control and Complication Trial)

DCCT (Diabetic Control and Complication Trial)

EDIC Study Epidemiology of Diabetes

Interventions and Complications Study

When to treat?

• Loss of vision

• Clinically significant macular edema

• Retinal ischemia

• Neovascularization

• Vitreous hemorrhage

• Consistent vitreous – macular traction

Severe Nonproliferative Diabetic

Retinopathy (NPDR)

Venous

beading

High-Risk Proliferative diabetic

retinopathy

At risk for serious vision loss

Any combination of three of the following four findings

• Presence of vitreous or preretinal hemorrhage.

• Presence of new vessels (neovascularization, NV)

• Location of NV on or near the optic disc.

• Moderate to severe extent of new vessels.

Proliferative diabetic retinopathy

Neovascularization

Hard exudate

Cotton-wool

spotspot

Blot hemorrhage

Proliferative papillary retinopathy

Haemovitreous

Options for the treatment

• Laser photocoagulation: current

standard of care for proliferative

retinopathy or vasogenic CSME

• Anti-VEGFcompounds [RBZ, Aflibercept (VEGF

Trap)]

• Steroid implants (dexamethasone, fluocinolone

acetonide)

• Vitrectomy

Panretinal photocoagulation reduced

the incidence of severe vision loss

from proliferative retinopathy by 50%

Laser photocoagulation for DME

Limitations of treatment

o does not eliminate possibility of further vision loss

o improvement in visual acuity is uncommon

o complications including permanent damage to the retinal

pigment epithelium and secondary choroidal neovascularization

36

National Eye Institute, National Institutes of Health. Diabetic Retinopathy. http://www.nei.nih.gov/health/diabetic/retinopathy.asp#4a

Accessed February 2009

AAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009

Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005.

http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf.

PASCAL =

pattern scanning laser

Micropulse mode

Dorin G. Semin Ophthalmol 2003; 18:147-153

Laser in DME

• Il trattamento Laser per lo piu’ non migliora la visione

Trial Cambiamento medio

VA con laser

DRCR.net Grid laser vs. IVTA 1 letter

DRCR.net Mod Macular Grid 0 letters

DRCR.net Ranibizumab vs.

prompt/ deferred laser/ IVTA

3 letters

RESTORE 1 letter

BOLT -4.6 letters

Diabetic Retinopathy Clinical Network. Ophthalmology 2008;115:1447-59e10; Diabetic Retinopathy Clinical Network. Ophthalmology

2010;117:1064-77; Mitchell et al. Ophthalmology 2011 118:615-25; Michaelides et al. Ophthalmology 2010;117:1078-86

Ranibizumab

Ranibizumab è un frammento di un anticorpo monoclonale umanizzato che si lega specificatamente e inibisce tutte le isoforme biologicamente attive del VEGF-A

Recettori

VEGF-A

VEGF-A Ranibizumab

Krzystolik et al. Arch Ophthalmol 2002; 120: 338-346 VEGF, fattore di crescita vascolare endoteliale

Inibisce il legame del VEGF-A con

i recettori VEGF, prevenendo la

cascata degli eventi che conduce

all’angiogenesi:

Inibisce la permeabilità

vascolare

Inibisce la proliferazione

endoteliale

Inibisce la migrazione delle

cellule endoteliali

Fase II: RESOLVE (Safety and Efficacy of Ranibizumab in Diabetic Macular Edema)

Massin P,. Diabetes Care 2010 *Tutti i pazienti, gruppi A+B

Set completo di analisi, LOCF

La prima misurazione post-basale di VA era stata effettuata al giorno 8

Fase II: RESOLVE (Safety and Efficacy of Ranibizumab in Diabetic Macular Edema)

Massin P,. Diabetes Care 2010

*Tutti i pazienti, gruppi A+B

Set completo di analisi, LOCF

La prima valutazione post-basale di CRT è stata effettuata il giorno 8

CRT, central retinal thickness

Fase II: Read-2 study

Ranibizumab 0.5 mg PRN Laser Laser PRN

Months 0 1 2 3 4 5 6 7-24 24-36

Group 1: Ranibizumab 0.5 mg

Group 2: Laser

Group 3: Ranibizumab 0.5 mg + laser

Treatment Initiation Phase* Retreatment phase† Retreatment phase‡

Ranibizumab 0.5 mg

*Treatment criteria: Ranibizumab 0.5 mg at baseline, Months 1, 3, and 5 (fixed regimen) for the ranibizumab 0.5 mg group; laser at baseline and again at Month 3 if CSFT ≥250 μm for the laser treatment group; ranibizumab 0.5 mg + laser treatment (always administered 1 week after ranibizumab) at baseline and Month 3 for ranibizumab 0.5 mg + laser treatment group †Retreatment criteria: Ranibizumab 0.5 mg no more than every 2 months or laser no more than every 3 months if the CSFT ≥250 μm; after the primary endpoint (Month 6), if retreatment criteria were met, patients in the RBZ group were treated with 0.5 mg RBZ, patients in the laser group could be treated with laser or RBZ, and patients in the combination group could receive laser plus RBZ or RBZ alone ‡Retreatment criteria: Ranibizumab 0.5 mg given as frequently as monthly if CSFT ≥250 μm

CSFT: center subfield thickness; PRN: pro re nata; RBZ: ranibizumab

Nguyen QG et al. Ophthalmology 2009;116(11):2175-81.e1 Nguyen QG et al. Ophthalmology 2010;117(11):2146-51 Do D et al. Arch Ophthalmol 2013; 131(2):139-145

9

-1

7

5

3

1

11 Ranibizumab 0.5 mg (n = 28) Laser (n = 22) Ranibizumab 0.5 mg + laser (n = 24)

Baseline Month 6 Month 12 Month 24 Month 36

Me

an c

han

ge in

B

CV

A, E

TDR

S le

tte

rs

p = 0.1

p = 0.009

p = 0.3

10.3

1.4

8.9

Patients included in the analysis were those who completed 36 months and the patients who completed 33 months or above; LOCF method was used to impute missing values; statistical comparisons made between Month 24 and Month 36 values for the same group of patients were calculated using the Wilcoxon signed rank test; BCVA: best-corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; LOCF: last observation carried forward

There was a significant BCVA improvement of 3.1 ETDRS letters at Month 36 for the patients in ranibizumab group when compared with the Month 24

There was an improvement of 2.0 letters in the ranibizumab + laser group and decline of 1.6 letters in the laser group at Month 36 when compared with Month 24

Ranibizumab allowed as of Month 6

READ-2

49 Do D et al. Arch Ophthalmol 2013; 131(2):139-145

Fase II: Read-2 study

200

250

300

350

400

450

500

Ranibizumab 0.5 mg (n = 28) Laser (n = 22) Ranibizumab 0.5 mg + laser (n = 24)

Baseline Month 6 Month 12 Month 24 Month 36

LOCF method was used to impute missing values; statistical comparisons made between Month 24 and Month 36 values for the same group of patients using the Wilcoxon signed rank test CSFT: center subfield thickness; LOCF: Last observation carried forward

p = 0.12

p = 0.006

p = 0.14

Mea

n f

ove

al t

hic

knes

s, µ

m

282

265

226

Patients in the ranibizumab monotherapy group showed a significant reduction of mean CSFT by 70 µm from Month 24 to Month 36

READ-2

50 Do D et al. Arch Ophthalmol 2013; 131(2):139-145

Fase II: Read-2 study

Treatment exposure

Overall, patients treated with ranibizumab 0.5 mg + laser and laser monotherapy groups received numerically a lower number of intravitreal ranibizumab 0.5 mg injections compared with those treated with ranibizumab 0.5 mg

Intravitreal ranibizumab 0.5 mg injections when combined with laser therapy may reduce the frequency of ranibizumab re-treatments

The mean number of ranibizumab injections during Year 3 was significantly greater in the ranibizumab group compared with the laser group (p = 0.008) but not when compared with the ranibizumab + laser group (p = 0.11)

Starting Month 6, patients were eligible to receive 0.5 mg ranibizumab or laser PRN treatment if CSFT ≥ 250µm; *n = 33, 34, 34 and †n = 28, 22, 24 for Groups 1, 2, 3 respectively CSFT: center subfield thickness; PRN: pro re nata

Treatment Groups Ranibizumab 0.5 mg injections

Month 6 to Month 24* Total* Year 3†

Group 1 (Ranibizumab 0.5 mg) 5.3 9.3 5.4

Group 2 (Laser) 4.4 4.4 2.3

Group 3 (Ranibizumab 0.5 mg + laser) 2.9 4.9 3.3

Nguyen QG et al. Ophthalmology 2009; 116(11):2175-81.e1 Nguyen QG et al. Ophthalmology 2010; 117(11):2146-51 Do D et al. Arch Ophthalmol 2013; 131(2):139-145

Ranibizumab

+Prompt Laser

N = 187

Ranibizumab

+Deferred Laser

N = 188

Sham

+Prompt Laser

N = 293

Triamcinolone

+Prompt Laser

N = 186

Occhi randomizzati:

N = 854 (691 Partecipanti)

Anno 1: visite ogni 4 settimane

Anno 2 e 3: iniezioni sham sospese e visite ogni 4-16 settimane

Prompt laser 3-10 giorni dopo iniezione.

Deferred laser non prima della settimana 24

Elman MJ, Ophthalmology 2010

Fase III: DRCR.net

53

0

1

2

3

4

5

6

7

8

9

10

11

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104

Sham+prompt laser

Ranibizumab+prompt laser

Ranibizumab+deferred laser

Triamcinolone+prompt laser

Primary outcome time point

* Values that were ±30 letters were assigned a value of 30

P-values for difference in mean change in visual acuity from sham+prompt laser at the 52-week visit:

ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.31.

Fase III: DRCR.net

Elman MJ, Ophthalmology 2012

Fase III: DRCR.net

RBZ+deferred laser

RBZ+prompt laser

+9,7

+6,8

Elman MJ, Ophthalmology 2012

Fase III: DRCR.net

RBZ+deffered laser

RBZ+prompt laser

- 152 µm

- 174 µm

Sham

+Prompt

Laser

Ranibizumab

+Prompt

Laser

Ranibizumab

+Deferred

Laser

Triamcinolone

+Prompt

Laser

No. iniezioni 1° anno n/a 8 9 3

No. iniezioni 2° anno

n/a 2 3 1

No. iniezioni 3° anno n/a 1 2 n/a

Fase III: DRCR.net

Fase III: RESTORE

Fase III, doppio cieco

N=315

Valutazione dell’efficacia e della

sicurezza con iniezioni mensili di

ranibizumab (0.5 mg) come terapia

aggiuntiva alla fotocoagulazione laser

e/o monoterapia in pazienti con visual

impairment dovuto a DME

12 mesi con estensione in aperto a 36

mesi

Obiettivo primario: dimostrare la superiorità di Ranibizumab (0.5mg) in monoterapia e/o in

terapia aggiuntiva al trattamento laser vs terapia laser basandosi sui cambiamenti medi di AV

rispetto al basale in un periodo di trattamento di 12 mesi

Iniziezione

sham

Diminuzione visiva

causata da DME

Randomizzati 1:1:1

N=315

Sham laser Active laser

111

Ranibizumab

0.5 mg

86

Ranibizumab

0.5 mg

118

Active laser

+7.9 +7.9

+7.1 +6.7

+2.3

+5.4

-2

0

2

4

6

8

10

12

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

Var

iazi

on

e m

ed

ia in

BC

VA

dal

bas

ale

(l

ette

re E

DR

S)

Mesi

Ranibizumab 0.5 mg (n = 83) Ranibizumab 0.5 mg + laser (n = 83) Laser (n = 74)

Core study assessment Interim Analysis Full analysis/Study

completion

Core study Extension study (Ranibizumab 0.5 mg PRN)

+8.0

+6.7 +6.0

59

I pazienti trattati dal primo anno con ranibizumab mantengono il miglioramento

medio della BCVA a 36 mesi

I pazienti trattati con laser il primo anno e poi passati a un trattamento con

ranibizumab hanno un miglioramento medio progressivo della BCVA dal mese

12 al mese 36

Mitchell P et al. AAO Nov 2012 PO532

Fase III: RESTORE

VEGF TRAP EYE/

AFLIBERCEPT

• Similar to ranibizumab and bevacizumab,

aflibercept binds to all isomers of the VEGF-A

family.

• Additionally, aflibercept binds to VEGF-B and

placental growth factor; it is hypothesized that

by blocking these factors, aflibercept may

prove to be more efficacious

Randomised controlled trials

of vitrectomy surgery for PDR

Randomised controlled trials

of vitrectomy surgery for DME

Algoritmo di trattamento per DME

Bandello et all:Treatment Recommendations for DME, Eye 2012,1-9

76

Management Paradigms for Diabetic Macular Edema

Paul Mitchell, Tien Yin Wong

Linee guida per lo screening, la diagnostica e il

trattamento della RD in Italia: aggiornamento 2013