Update on Diabetic Eye Disease

Management

Dr Fred Chen

MBBS(Hons), PhD, FRANZCO

Consultant Ophthalmologist

Medical and Surgical Retina

Head, Ocular Tissue Engineering Laboratory, UWA

Director of Clinical Research, Lions Eye Institute

GP education event

2 September 2017

Summary

What’s new in diabetic eye diseases?

Clinical assessment

Treatment options

Treatment outcomes

Rank 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

1 Atorvastatin Atorvastatin Atorvastatin Atorvastatin Atorvastatin Atorvastatin Atorvastatin Rosuvastatin Adalimumab Ledipasvir + sofosbuvir

2 Simvastatin Esomeprazole Rosuvastatin Rosuvastatin Rosuvastatin Rosuvastatin Rosuvastatin Adalimumab Rosuvastatin Adalimumab

3 Esomeprazole Simvastatin Esomeprazol

e Ranibizumab Ranibizumab Ranibizumab Esomeprazole Esomeprazole Aflibercept Ranibizumab

4 Clopidogrel Clopidogrel Clopidogrel Adalimumab Salmeterol/Fl

uticasone Ranibizumab Sofosbuvir

5 Salmeterol/Fluti

casone Salmeterol/Flu

ticasone Salmeterol/Fl

uticasone Salmeterol/Fl

uticasone Atorvastatin

Salmeterol/Fluticasone

Aflibercept

6 Olanzapine Rosuvastatin Simvastatin Ranibizumab Aflibercept Esomeprazole Esomeprazole

7 Omeprazole Olanzapine Ranibizumab Aflibercept Ranibizumab Etanercept Etanercept

8 Venlafaxine Venlafaxine Fluticasone +

salmeterol

9 Pantoprazole Pantoprazole Fingolimod

10 Tioptropium Br Ranibizumab Insulin

Glargine

PBS Drugs sorted by highest government cost 2007-2016

146,736 Lucentis dispensed (and injected into the eye)

142,372 Eylea dispensed (and injected into the eye)

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Maculopathy

Neovascularisation

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Maculopathy

Neovascularisation

Optic Nerve

Lens Cornea

Fovea

Posterior Pole of the retina

Equatorial region of the retina

Macula Cataract Macular Disease

Refractive Errors

Glaucoma

Trachoma

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Maculopathy

Neovascularisation

At 6 m At 4 m

6/60 = 35

6/24 = 55

6/12 = 70

6/6 = 85

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Maculopathy

Neovascularisation

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Maculopathy

Neovascularisation

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Maculopathy

Neovascularisation

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Maculopathy

Neovascularisation

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Maculopathy

Neovascularisation

Superficial

capillary slab

Deep capillary

slab

Chorio-

capillaris slab

Choroidal

slab

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Neovascularisation

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Retinopathy

Neovascularisation

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Retinopathy

Neovascularisation

Clinical Assessment of Diabetic Eye

Disease

Neuropathy

Motor: cranial nerve III, IV, VI

Sensory: cranial nerve V (trigeminal) – cornea

Retinopathy

Maculopathy

Neovascularisation

Don’t forget Cataract and Refractive Error Change

Treatment Options in Diabetic Eye

Disease

Retinopathy

Maculopathy

Anti-VEGF / Steroid injections

Laser

Surgery

Neovascularisation

Laser

Anti-VEGF injections

Surgery

Vascular endothelial growth factor

• Identified in 1983

• Structure in 1996

• Hypoxia stimulate release

• Restore oxygen supply

• Vasculogenesis, angiogenesis, lymphangiogenesis

• Naturally higher in asthma, diabetes

• Pathologically higher in solid cancers, retinopathy

• Family of 5 GF: VEGF-A, B, C, D, Placental GF

• Binds to a tyrosine kinase receptor and neuropilin co-

receptor

• Monoclonal antibody – Bevacizumab (Avastin)

• Variation 1:

– Antibody fragment (Use the Fab portion) – Ranibizumab (Lucentis)

• Variation 2:

– Fc-Fusion protein (Use the Fc portion) – Aflibercept (Eylea)

Anti-vascular endothelial growth factor Drugs

• Abicipar pegol – Design ankyrin repeat protein (DARPin)

– Allergan

• Bolucizumab – ESBA-1008 / RTH-258

– Alcon

• Conbercept – Fusion of IgG and key domains of VEGFR

– Chengdu Kanghong Pharmaceuticals

Intravitreal injection procedure

• Topical anaesthetic (sub conj)

• Povidone iodine / Chlorhex wash

• 3-4 mm behind cornea

• 30G needle

• 0.05 mL of solution squirted in

Process (1-2 hours):

1. Visual acuity

2. OCT scan

3. Review VA/OCT

4. Determine retreatment schedule

5. Injection (1-2 mins)

6. Eye wash

Treatment Outcomes in Diabetic Eye

Disease

Retinopathy

Maculopathy

Anti-VEGF / Steroid injections

Neovascularisation

Laser +/- anti-VEGF

Vitrectomy

Anti-VEGF vs Steroid

Anti-VEGF (intravitreal)

Avastin: solution

Lucentis: soluion

Eylea: solution

Steroid (intravitreal)

Triamcinolone (Kenacort A40): suspension

Dexamethasone (Ozurdex implant): sustained release

Avastin DEX 0.70

Mean change BCVA 9.6 6.9

P = 0.30

Trend may be driven by phakic eyes developing cataract. 37% of eyes in the OZURDEX® group underwent cataract surgery

during the study, with subsequent improvement in vision by month 241

Adapted from Fraser-Bell S et al. 2016.

• Total patient population

Eyes with ≥10 letters gained (primary endpoint):

Bevacizumab = 19/42 (45%)

OZURDEX® = 20/46 (43%)

p=not significant

Mean improvement in BCVA letters [95% CI]:

Bevacizumab = 9.6 [6.9–12.3]

OZURDEX® = 6.9 [2.7–11.1]

p=not significant

Avastin DEX 0.70

Predicted ? ?

CMT change -122 -198

P = 0.015

CMT peaked at 4 and 8 month visits due to drug wearing off Adapted from Fraser-Bell S et al. 2016.

Avastin DEX 0.70

Number of injection 8.6 2.7

P = not reported

Trend may be driven by phakic eyes developing cataract.

Steroid induced high intraocular pressure

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 96100104

Sham+pr

ompt

laser

Ranibizu

mab+pro

mpt

laser

Primary outcome time point

DRCR.net study (lucentis, steroid, laser)

DA VINCI Study (Eylea)

Take Home Messages

Diabetic eye disease is not just retinopathy. It included sensory and

motor neuropathy as well as cataract and refractive error

Adequate clinical assessment requires sophisticated instrumentation

and clinical expertise in image interpretation from a Medical Retina

Fellowship to differentiate diabetic retinopathy from other rarer

vascular diseases

Treatment posology is evolving. Currently, anti-VEGF / steroid implant

for centre-involving macular oedema and pan-retinal laser for

proliferative disease with or without anti-VEGF are preferred 1st line.

Early surgical intervention by vitreoretinal surgeons may prevent

permanent blindness from fibrotic complications and failed anti-VEGF

therapy.

Funding support

NHMRC Fellowship, Project Grant

Medical Research Foundation of RPH

The University of Western Australia

Lions Eye Institute

Ophthalmic Research Institute of Australia

Retina Australia