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Diabetic Retinopathy: An Update for Diabetes

Educators

A. Paul Chous, M.A., O.D., F.A.A.O.

Private Practice -Tacoma, WA

Specializing in Diabetes Eye Care & Education

A. Paul Chous, MA, OD, FAAO

Author of Diabetic Eye Disease: Lessons

From a Diabetic Eye Doctor (Fairwood

Press, 2003)

Web columnist for www.dLife.com and

www.diabetesincontrol.com

Optometric representative to the National

Diabetes Education Program of the NIH

Winner of American Diabetes Association’s

Distinguished Public Service Award in 1998

T1DM x 45 years

Disclosures

I am or have been a consultant for, been on

advisory boards of, or spoken on behalf of:

Bausch & Lomb, Freedom

Meditech, GlaxoSmithKline,

Kestrel, Kowa, LifeMed Media,

Prodigy Diabetes Care, Risk

Medical Solutions, Vision

Service Plan, ZeaVision

None of these affiliations

have affected the content of

this presentation

Diabetes-Related Eye

Diseases

“Diabetic Eye Disease” refers to ocular

pathologies more commonly seen in

patients with diabetes

All of these conditions are attributable, at

least in part, to chronic hyperglycemia

Ocular Diseases Associated With Ocular Diseases Associated With

DiabetesDiabetes

CataractCataract

KeratopathyKeratopathy

Efferent Cranial NeuropathyEfferent Cranial Neuropathy

GlaucomaGlaucoma

Ischemic Optic NeuropathyIschemic Optic Neuropathy

Retinal Vascular OcclusionRetinal Vascular Occlusion

Diabetic RetinopathyDiabetic Retinopathy

Cataract

Corneal Disease

CN VI Palsy

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AION Branch Vein Occlusion

Iris Rubeosis Glaucomatous Optic Nerve

Diabetic Retinopathy (DR)

Chronic hyperglycemia unleashes a progressive cascade of events

Endothelial pericyte loss

Retinal Ganglion Cell (RGC) death

Increased vascular permeability

Capillary closure

Release of vasoproliferative factors

Neovascularization, fibrovascular vitreo-retinal adhesions, vitreous hemorrhage

“Diabetic Eye Diseases”

Another American becomes legally blind from diabetic retinopathy every 24 minutes

No independent tracking of irreparable vision loss from other eye diseases commonly associated with diabetes (retinal vascular occlusion, AION, glaucoma)

Realistic accounting might increase the toll from 12-24 thousand to 30,000+ cases per year

Normal Retina – Posterior Pole Diabetic Retinopathy

Most patients develop DR over time

60% at 10 yrs

90% at 20 yrs

Old statistics from WESDR – may be

improving with better metabolic

management

Minimizing the SEVERITY of DR is

the key to preventing vision loss

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DR Lesions

Microaneurysms: balloon-like outpouchings of normal retinal capillaries

Intra-retinal Hemorrhage: from faulty capillaries

Hard exudates: protein and fat leakage

Intra-retinal swelling: causes macular edema (DME)

Cotton Wool Spots: infarcted retinal nerve fibers

Vein Beading: signal ischemia

IRMA: precursors to abnormal new blood vessel

Neovascularization of optic nerve or retina or iris

Vitreous hemorrhage: vision loss

Traction retinal detachment: vision loss

Vitreous Hemorrhage

Traction RD

DME – The “Other” Diabetic Retinopathy Retinopathy LesionsRetinopathy Lesions

MicroaneurysmsMicroaneurysms (MA)(MA)

Dot & Blot HemorrhagesDot & Blot Hemorrhages

Hard ExudatesHard Exudates

Retinal ThickeningRetinal Thickening

Cotton Wool SpotsCotton Wool Spots

Vein BeadingVein Beading

IntraIntra--retinal retinal MicrovascularMicrovascular Abnormalities Abnormalities

(IRMA)(IRMA)

Neovascularization (of disk, retina or Neovascularization (of disk, retina or

iris/angleiris/angle) ) –– Proliferative Diabetic RetinopathyProliferative Diabetic Retinopathy

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What’s The Most Common

Symptom of DR and/or DME?

A. I see spots before my eyes (vitreous

floaters)

B. I see flashes of light before eyes (photopsia)

C. I am having trouble reading street signs

D. No symptoms whatsoever

3 Types of DR Non-proliferative DR (NPDR): no

neovascularization; typically no symptoms; most common form of DR

Proliferative DR (PDR): neovascularization of the optic ‘disk’ (NVD) or elsewhere on the retina (NVE); often no Sx unless retinal detachment or vitreous hemorrhage total blindness

Diabetic Macular Edema (DME): fluid damages photoreceptors vision loss but not total blindness; may occur in isolation or with NPDR or PDR

Staging of Diabetic Retinopathy

Proposed International Standard

No Apparent DR no retinal findings

Mild NPDR microaneurysms only

Moderate NPDR > ‘mild’ but < ‘severe’

Severe NPDR > 20 hemorrhages in 4 quads or definite vein beading in 2+ quads

or IRMA in 1+ quads (4-2-1 rule)

PDR definite NVD or NVE and/or VH/PRH

Ophthalmology, 2003 Sept: 110(9): 1677-82

ETDRS is the “Gold Standard”

Proliferative Diabetic Retinopathy

NVD or NVE

Untreated, can lead to

VH or tractional RD

Without tx, 50% blind in

5 years

Current treatment: PRP

when High Risk, may

need vitrectomy

Found in 25% of Type 1

by 15 yrs and Type 2 by

25 yrs

Staging of Diabetic Macular Edema

DME Absent no retinal thickening or hard

exudates in the posterior pole

DME Present some retinal thickening or hard exudates in the posterior pole

Mild DME RT or HE in the posterior pole but distant from the macula

Moderate DME RT or HE approaching but not

involving the macular center

Severe DME RT or HE involving the center

of the macula

ETDRS is the “Gold Standard”

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Macular Edema

3 evidence-based criteria for Tx Thickening <1/3DD from center of

macula

Heme/exudate with thickening of adjacent retina <1/3dd from center of macula

Thickening >1dd size within 1dd center

Current treatment: Grid/Focal laser; Intravitral injection of anti- VEGF drugs (Avastin/Lucentis)

DR – some real numbers

Pooled analysis from almost 23k Pooled analysis from almost 23k with with DMDM

•• 34.6% prevalence for any DR34.6% prevalence for any DR

•• 6.96% for PDR6.96% for PDR

•• 6.81% for DME6.81% for DME

•• 10.2% for 10.2% for Vision Threatening DR (PDR and/or DME)Vision Threatening DR (PDR and/or DME)

•• All DR end points increased with DM duration, AAll DR end points increased with DM duration, A1c1c & &

BPBP

Higher in people with T1DM compared w T2DM Higher in people with T1DM compared w T2DM

Worldwide: 93M w DR, 17M PDR, 21M Worldwide: 93M w DR, 17M PDR, 21M

DME, 28M VTDRDME, 28M VTDR Yao et al. Prevalence of DR. Diabetes Care . March 2012

Managing Diabetic

Retinopathy

Out, damned spot!

Out, I say! - Macbeth

Management of DR

Prevention of Diabetes!

Delay onset of DR by optimizing

metabolic control, patient education

and adherence to the treatment plan

Annual dilated eye exams

Laser and/or intravitreal injections for

STR as indicated

Blood Glucose ControlBlood Glucose Control

MetaMeta--analysis of the DCCT and UKPDS analysis of the DCCT and UKPDS

shows that:shows that:

This linear reduction in risk holds for This linear reduction in risk holds for

HbAHbA1C1C between 5% and 8%between 5% and 8%

Each 10% Reduction in HbAEach 10% Reduction in HbA1C1C

Lowers the Risk of DRT Lowers the Risk of DRT

Progression By 43%Progression By 43%

Drugs. 2010 Dec 3;70(17):2229-45.

The DCCT 20 Years LaterThe DCCT 20 Years Later

Intensive control of T1DM lowered the risk Intensive control of T1DM lowered the risk of DR 58% and nephropathy by 64% after of DR 58% and nephropathy by 64% after 30 years30 years

The risk of CV events was lowered by 36%The risk of CV events was lowered by 36%

After 30 years of T1DM, <1% of pts After 30 years of T1DM, <1% of pts assigned to intensive control during the assigned to intensive control during the DCCT suffered VA worse than 20/40, ESRD DCCT suffered VA worse than 20/40, ESRD or amputationor amputation

Arch Intern Med 2009;169(14): 1307-16

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Highlights from The ‘Big’ DR Studies

PRP reduces risk of severe vision loss (< 20/800) from PDR by 50-65% (DRS/ETDRS)

Focal laser reduces risk of doubling the visual angle by 50% in CSME (ETDRS)

Aspirin has no effect on PDR/VH (ETDRS)

Vitrectomy is indicated for non-clearing vitreous hemorrhage and tractional RD of the macula (DRVS)

Invest Ophthalmol Vis Sci 1981 : 210-226

Arch Ophthalmol 1985 Dec;103(12):1796-806

Arch Ophthalmol 1990;108: 958-964

RESTORE & READRESTORE & READ

LucentisLucentis versus Laser for Vision loss from versus Laser for Vision loss from

CSME (20/40 to 20/200 BCVA)CSME (20/40 to 20/200 BCVA)

Percent Percent achieving achieving >> 20/40 ETDRS acuity 20/40 ETDRS acuity

at 12 months:at 12 months:

LucentisLucentis –– 53%53%

LucentisLucentis + Laser + Laser –– 44.9%44.9%

Laser alone Laser alone –– 26.3%26.3%

Benefit of Benefit of LucentisLucentis maintained at 3 yearsmaintained at 3 years

No increased MI or CVA with No increased MI or CVA with LucentisLucentis Ophthalmology. 2011 Apr;118(4):615-25.

JAMA Ophthalmol. 2013 Feb;131(2):139-45

What’s Best for DMEWhat’s Best for DME??

antianti--VEGF treatments are VEGF treatments are

superior to macular laser for superior to macular laser for

VA and VA and retinal thickening retinal thickening

BUT…need repeat injections &

costs more money

Bevacizumab (AvastinTM) + Laser

most cost-effective comparing laser, steroid,

Lucentis, Avastin or any combination

Ophthalmology. 2013 May 1. epub

A Few Important

Considerations Regarding

Systemic Management of

Diabetes and DR

ACEIs/ARBs & Retinopathy

Vasotec® (enalapril) and Cozaar® (losartan)

reduced the risk of DR progression by 65%

and 70% in T1DM NEJM 2009;361: 40-51

Captopril reduces DR progression 40% and DME 30%

in T2DM

Should these agents become standard

treatment of DR?

-prils and –sartans may

lower DR Risk of Progression

Chin Med J (Engl) 2012 Jan;125(2):287-92

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Lipid Agents & Retinopathy

Simvistatin + Fenofibrate therapy lowers the risk of DR progression by 35% (and need for laser by 31%) compared to simvistatin alone in pts with T2DM and high cardiovascular risk (n = 2856)

Consistent with FIELD Study showing reduced progression of DR and need for laser Tx Lancet 2007 370(9600):687-97

ACCORD Eye Study, N Engl J Med. 2010 Jul 15;363(3):233-44

Add-on Fenofibrate lowers risk of DR progression in T2DM

TZDs & DME Retrospective cohort study of 103K+

T2DM patients suggests use of

rosiglitazone or pioglitazone more

than doubled the risk of DME (3x risk

with concomitant insulin use –

attenuated by ASA and especially

ACEI use)

Probably wise to avoid or D/C

glitazones in patients with DME

Arch Intern Med. 2012 Jul 9;172(13):1005-11

More to Retinopathy than Retinopathy

Retinopathy predicts CV mortality and

coronary heart disease (CHD)1

PDR>NPDR>no retinopathy in likely CVD and CHD

mortality, and women>men, especially in NPR

In women, PDR yields nearly 5x risk of CHD death!

Independent of smoking, HTN, Cholesterol, HDL,

duration or control of DM or proteinuria

Retinopathy predicts stroke rate2

Those with DR have 2.34x risk for ischemic stroke

Independent of smoking, cholesterol, insulin use,

HTN

1. Diabetes Care. Feb. 2007;30:292-99. 2. Cheung et al. Stroke. Feb 2007

Can We Predict Who is Going to

Develop Sight-threatening

Diabetic Retinopathy?

Risk Factors For Diabetic

Retinopathy Established

Disease duration

HbA1c

Disease sub-type

Gender

HTN

Microalbuminuria

Emerging

Obesity

Sleep apnea

Vitamin D insufficiency

Vit B12 deficiency

Carotenoid imbalance

Invest Ophthalmol Vis Sci. 2011 Jun 22;52(7):4416-21

Diabet Med. 2010 Apr;27(4):423-30

Endocr Pract. 2012 Mar-Apr;18(2):185-93

PLoS One. 2011;6(11):e26747

Obstructive Sleep Apnea Syndrome

OSAS is independently associated with risk of

DR and its progression

Br J Ophthalmol. 2012 Dec;96(12):1535 Retina. 2012 Oct;32(9):1791-8.

Jpn J Ophthalmol. 2011 Nov;55(6):638-42

Am J Ophthalmol. 2011 Apr;151(4):604-9

Mil Med. 2010 Nov;175(11):913-6 Diabet Med. 2010 Apr;27(4):423-30

Am J Ophthalmol. 2009 Jun;147(6):1017-21

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PDR Risk PDR Risk Goes Up WithGoes Up With::

Higher HbA1cHigher HbA1c: : each 1 pt increase each 1 pt increase

in pts with NPDR raises PDR risk in pts with NPDR raises PDR risk

14%14%

NonNon--healing limb ulcers healing limb ulcers increased increased

risk of PDR by 54%risk of PDR by 54%

Diabetic Kidney Disease Diabetic Kidney Disease

increases risk of PDR by 29%increases risk of PDR by 29%

Retrospective cohort analysis of 4617 DM

pts with NPDR at Univ. of Michigan Eye Center

Diabetes Care. 2013 Jan 3

C-reactive Protein & CSME

• Blood samples from 1441 DCCT

subjects

• Analyzed for ICAM, TNF-a and hsCRP

• Highest quartile of hsCRP linked to

83% increased risk of CSME vs lowest

quartile JAMA Ophthalmol. 2013 Feb 7:1-8.

Is it Important Prevent Is it Important Prevent Blood Glucose Blood Glucose

Spikes?Spikes?

AKA “PostAKA “Post--prandialprandial Hyperglycemia” or Hyperglycemia” or

““GlycemicGlycemic excursions”excursions”

DCCT:

Retinopathy developed

more often in pts

receiving “conventional Tx” at HbA1c Levels

equal to those in the “intensive Tx” group

A1c Variability Matters!

• 5 year cumulative incidence of laser

Tx for DR in 1459 T1DM pts with

highest (19%) vs lowest (10%) A1c

variability controlling for mean A1c,

duration, BP, kidney status, gender

– 70% increase risk of PDR in hi SD group

Diabetologia. 2013 Jan 13

STR STR Risk CalculatorRisk Calculator

Risk calculator for STR (PDR and/or Risk calculator for STR (PDR and/or CSME) based on a few simple inputsCSME) based on a few simple inputs

•• DM subDM sub--type, gender, age, HbA1c, BP, type, gender, age, HbA1c, BP, presence and severity of NPDRpresence and severity of NPDR

Excellent predictive accuracy when Excellent predictive accuracy when compared to outcomes from the Danish compared to outcomes from the Danish Diabetes Cohort (n=5199 followed for 20 Diabetes Cohort (n=5199 followed for 20 yrs)yrs) Diabetologia. 2011 Oct;54(10):2525-32.

Q: How effective in a diverse, multicultural society?

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If our patient can reduce HbA1c to the AACE Target of 6.5%

the 10 year risk of developing sight-threatening

retinopathy drops to 19.8%, or by 39%

www.Retinarisk.com

Gold MedalistsGold Medalists

Time/Metabolic Control Time/Metabolic Control may not be may not be

the only the only enemyenemy……

“Medalists”: h/o T1DM x 50yrs “Medalists”: h/o T1DM x 50yrs

42.642.6% did not have PDR, and those % did not have PDR, and those

without had little progression of DR without had little progression of DR

after after first first 17yrs17yrs

With little to no correspondence to A1cWith little to no correspondence to A1c Diabetes Care. 2011 Apr;34(4):968-74

Key Message

Most blindness and severe visual

impairment caused by diabetic

retinopathy is preventable with

good diabetes self-management,

regular dilated eye examinations

and timely treatment

Diabetes & DR Affect Visual

Function

Snellen visual acuity is a 150+ yr old

test that does not always reflect real

world visual function

DM/DR also impair: color perception,

contrast sensitivity, visual field sensitivity

Graefes Arch Clin Exp Ophthalmol. 2012 Dec;250(12):

Diabet Med. 2011 Jul;28(7):865-71

Acta Opthalmol 2005; 82(5):574-80

Graefes Arch Clin Exp Ophthalmol. 2001 Sep;239(9):643-8 BJO 1996;80: 209-13

IOVS 1997; 38(9): 1819-24

Diabetes Care 1992; 15(5):620-25

Graefes Arch Clin Exp Ophthalmol. 1996 May;234(5):300-5

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Vision in The Real World

It may be time to develop, test and educate ECPs, PCPs & the public

about an AREDS-2 type multi-component supplement for patients

with diabetes and diabetic retinopathy

Beyond AREDS: is there a place for antioxidant therapy in

the prevention/treatment of eye disease?

Kowluru RA, Zhong Q.

Invest Ophthalmol Vis Sci. 2011 Nov 7;52(12):8665-71

Diabetes

Growth Factors TGF PDGF BDNF

IGF VEGF PEDF

Hypertension

Hyperglycemia hMitochondrial ROS

Dyslipidemia Atherogenic LDL

Hormones Cortisol

GH

RAAS

AGEs

ET-1

AGEs Hexosamine PKC Polyol

Oxidative

Stress

Apoptosis RGCs/Inner Retina

Capillary Endothelium

Inflammation NFkB

TNF-a, IL-6, MMP, kallikrein, ICAM

Diabetic Retinopathy BRB Breakdown

Hypoxia/Neovascularization

6 month placebo6 month placebo--controlled RCCT of adults controlled RCCT of adults with T1DM or T2DM with T1DM or T2DM >> 5 years5 years

With and without retinopathyWith and without retinopathy

Daily use of a multiDaily use of a multi--component nutritional component nutritional supplement supplement ((luteinlutein, , zeaxanthinzeaxanthin, D, C, , D, C, E, Zn, E, Zn, curcumincurcumin, , benfotiaminebenfotiamine, Pycnogenol, , Pycnogenol, lipoiclipoic acid, NAC, acid, NAC, resveratrolresveratrol, , grapeseedgrapeseed extract, green tea, extract, green tea, OO--3 FAs, CoQ10)3 FAs, CoQ10)

Contrast sensitivity, Contrast sensitivity, color vis., macular color vis., macular perimetryperimetry, OCT, A1c, lipids, 25(OH) , OCT, A1c, lipids, 25(OH) vitvit. D, . D, TNFTNF--a, a, hsCRPhsCRP, DPNS, DPNS

Diabetes Visual Function Supplement Study

(DiVFuSS)

ClinicalTrials.gov Identifier: NCT01646047

Animal Model of DR

• DiVFuSS formula blocked early

mitochondrial damage in rats

• DiVFuSS formula blocked retinal

capillary apoptosis underlying DR

• DiVFuSS formula improved b-wave

ERG (retinal function)

Presented at ARVO 2013, Seattle

IOVS, awaiting publication

First 46 subjects to complete trial

DiVFuSS

Unmasked

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Subject Characteristics (n = 46)

31-79 yo (mean = 56 yrs)

25 with NPDR & 21 with no DR

18 T1DM & 28 T2DM

HbA1c range 5.8 to 9.3% (mean 7.4%)

Mean A1c in those with DR = 7.8%

Mean A1c in those with no DR = 7.1%

Diabetes duration 5-52 years (mean 21.2 yrs)

Mean 23.4 years in those with DR

Mean 14.7 years in those with no DR

DiVFuSS Unmasked Data Δ from baseline Supplement versus Placebo

Contrast: +31% -20%

Color Error Score: -50% -2%

5-2 MD: +1.1 dB +0.17 dB

hsCRP: -72% +10%

HbA1c: -4% +2.5%

OCT mean NFL: unchanged in both groups

For contrast, color, visual field, hsCRP, p < 0.02

Mean Contrast For S and P Groups Pre- and Post Trial

Summary of Early Findings in Human Subjects

• DiVFuSS formula improved visual

function, including contrast sensitivity,

visual field sensitivity and color

perception

• DiVFuSS formula significantly

reduced hsCRP and DPN scores

Getting Patients to Buy In to Good

Diabetes Self-Management

YOU are the experts

Here are my thoughts as

a patient & a provider……..

Good Public Health and Economics Good Public Health and Economics

Suggest that we should…Suggest that we should…

Make it “cheap” to practice good self Make it “cheap” to practice good self

care & incentivize good health habitscare & incentivize good health habits

Screen for and manage depressionScreen for and manage depression

Educate and reEducate and re--educate patientseducate patients

Diabetes doesn’t cause Diabetes doesn’t cause

complications. Poorly controlled complications. Poorly controlled

diabetes causes complications diabetes causes complications

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My ExperienceMy Experience

Scare tactics generally Scare tactics generally

don’t don’t work, if at all, until patients work, if at all, until patients

have lost somethinghave lost something

Scare tactics and threats aren’t Scare tactics and threats aren’t

conducive to good relationshipsconducive to good relationships

Building a relationship worksBuilding a relationship works

“If you want to tell

someone the truth,

first make them laugh.

Otherwise they will

kill you.”

- Oscar Wilde

Getting Patients To Buy In

Use humor

Tell patients about your personal or family

experiences with diabetes

Criticize behaviors, not the person

Use patient Handouts & Digital Imaging

Conference with the patient & family

As a last resort for men, the risk of

impotence can be a very strong motivator

Various research indicates that men think about sex Q 6-8 seconds

The Most Important Message A

Health Care Professional Can

Convey To Patients Living With

Chronic Disease, Including

Diabetes:

“I Am On

Your Side”

The Most Important Message A

Health Care Professional Can

Convey To Other Members of

the Diabetes Care Team…

“The only way to keep your health

is to eat what you don't want, drink

what you don't like, and do what

you'd rather not.”

“Get your facts first, then you

can distort them as you please”

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Thank You!Thank You!

A. Paul A. Paul ChousChous, MA, OD, FAAO, MA, OD, FAAO

dr.chous@diabeticeyes.comdr.chous@diabeticeyes.com