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NewFron)ersintheDetec)on&ManagementofDiabe)cRe)nopathy

A.PaulChous,MA,OD,FAAO,CDEChousEyeCareAssociatesTacoma,Washington

TheseaffiliaConswillnotaffectthecontentofthispresentaCon

FinancialDisclosures

•  Bausch&Lomb•  Genentech•  Konan•  Regeneron•  ZeaVision•  Zeiss

A.PaulChous,OD

Objec)ves•  Epidemiology&DemographicTrends

• WhatISDiabe)cRe)nopathy

• What’sNewforDetec)ngDiabe)cRe)nopathy

•  Assaul)ngDiabe)cRetnopathy

•  Preven)on&Optometry’sRole

WorldwideSta)s)cs

n 1billionwillhavediabetesby2050

n Highestincreasesindiabetes&prediabetesinAsiaandSub-SaharanAfrica

InternaConalDiabetesFederaCon,2015;www.diabetesatlas.org

2017CDCDiabetesSta)s)cs

•  30.3millionAmericans•  7.2millionundiagnosed•  84.1millionhaveprediabetes•  1.4millionlegallyblindfromDR

NaConalDiabetesStaCsCcsReport2017USCentersforDiseaseControl&PrevenConAccessedath]ps://www.cdc.gov/diabetes/pdfs/data/staCsCcs/naConal-diabetes-staCsCcs-report.pdf

IncreasingPrevalenceofDiabetesOverTime

2015

Improvementsintherapiesandmedicalmanagementover3mearefactoredin

7-8% 11-12% 19-20% 13-14% 17-18%

Percent of Total Population with Diabetes (Diagnosed and Undiagnosed) 9-10% 15-16%

Institute for Alternative Futures 2014 Diabetes Model based on Boyle, Projection of the year 2050 burden of diabetes in the US adult population, http://www.pophealthmetrics.com/content/8/1/29 ; CDC, National Diabetes Statistics Report, 2014; CDC diabetes trends; US Census Bureau Population Statistics

IncreasingPrevalenceofDiabetesOverTimeImprovementsintherapiesandmedicalmanagementover3mearefactoredin

7-8% 11-12% 19-20% 13-14% 17-18%

Percent of Total Population with Diabetes (Diagnosed and Undiagnosed) 9-10% 15-16%

Institute for Alternative Futures 2014 Diabetes Model based on Boyle, Projection of the year 2050 burden of diabetes in the US adult population, http://www.pophealthmetrics.com/content/8/1/29 ; CDC, National Diabetes Statistics Report, 2014; CDC diabetes trends; US Census Bureau Population Statistics

2020

IncreasingPrevalenceofDiabetesOverTimeImprovementsintherapiesandmedicalmanagementover3mearefactoredin

7-8% 11-12% 19-20% 13-14% 17-18%

Percent of Total Population with Diabetes (Diagnosed and Undiagnosed) 9-10% 15-16%

Institute for Alternative Futures 2014 Diabetes Model based on Boyle, Projection of the year 2050 burden of diabetes in the US adult population, http://www.pophealthmetrics.com/content/8/1/29 ; CDC, National Diabetes Statistics Report, 2014; CDC diabetes trends; US Census Bureau Population Statistics

2025

IncreasingPrevalenceofDiabetesOverTimeImprovementsintherapiesandmedicalmanagementover3mearefactoredin

7-8% 11-12% 19-20% 13-14% 17-18%

Percent of Total Population with Diabetes (Diagnosed and Undiagnosed) 9-10% 15-16%

Institute for Alternative Futures 2014 Diabetes Model based on Boyle, Projection of the year 2050 burden of diabetes in the US adult population, http://www.pophealthmetrics.com/content/8/1/29 ; CDC, National Diabetes Statistics Report, 2014; CDC diabetes trends; US Census Bureau Population Statistics

2030

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Diabe)cRe)nopathy•  Almost5%ofUSadultswithdiabeteshavesight-threateningdiabe)cre)nopathy

•  SignificantlyhigherinAfrican-Americans,La)noandNa)veAmericanethnicgroups

• Macularedema(DME)isthebiggestcauseofvisionloss

•  Improvingbloodglucose&bloodpressurecontrollowerstheriskofdiabe)cre)nopathyanditsprogression– diseasedura)onmostimportantriskfactor

•  Nolevelofaveragebloodglucoseistotallyprotec)veagainstdiabe)cre)nopathy

FrankRN.Diabe)cRe)nopathyandSystemicFactors.MiddleEastAfricanJournalofOphthalmology.2015;22(2):151-156.

US = 30 million India = 60 million China = 100 million With Diabetes

483

Blue Things

• Worldwidediabetesprevalenceisnow483million

•  Halfofpeoplewhohavediabetesareundiagnosed

•  Fivemilliondeathsa_ributabletodiabetesin2017–halfofthesewereinpa)ents<60yo

•  Youorthepersonnexttoyoualmostcertainlyhasorsoonwillhavediabetesorprediabetes DiabetesResClinPract.2018Apr;138:271-281

CostofDiabetestotheUSEconomy

•  $327Billionin2017– $92Billioninlostpoduc)vity– 1in4healthcaredollars

•  Upfrom$245Billionin2012•  26%increaseageradjus)ngforinfla)on

DiabetesCare.2018May;41(5):917-928

USPROJECTEDFUTUREPREVALENCEOFDIABETES

1 in 10 2012

ü Significant increase in prevalence of total

diagnosed and undiagnosed diabetes in adults in the US over the next 40 years.

1 in 3 to 5 2050

BoyleJP,etal.Popula3onHealthMetrics.2010;8:29.h]p://www.pophealthmetrics.com/content/8/1/29.AccessedFebruary11,2015.

MeanEs)mate:100millionAmericansby2050

OcularAffectsofDiabetes

•  Diabetescanproduceanyofthefollowingophthalmicmanifesta)ons

• Refrac)vechangesOcularsurfacedisease• GlaucomaandcataractsDiabe)cvitreopathy• CranialnervepalsiesDeficitsinvisualfunc)on•  Re)nalvascularocclusion • Diabe)cre)nopathyDiabetesandDRaffectmorethanvisualacuity

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WhatISDiabe)cRe)nopathy?

•  Microvasculardiseasedetectedbyobserva)onofvascularabnormaliCes

•  ReCnalneuro-degeneraConwithloss/derangementofneuralelementsincludingganglioncellbodies,nervefiberlayer,andphotoreceptorscausinglossofvisualfunc)on

JacksonGR,Sco]IU,QuillenDA,WalterLE,GardnerTW.InnerreCnalvisualdysfuncConisasensiCvemarkerofnon-proliferaCvediabeCcreCnopathy.Bri3shJournalofOphthalmology2012;96:699-703

Twodis)nctbutinter-relatedprocesses

DR IS NOT ONLY THIS STUFF

IT’S ALSO THIS STUFF

Diabe)cRe)nopathy(&diabeteswritlarge)isaNeurovascularDisease

Re)nalNeurodegenera)on•  Lossofganglioncellbodies•  Glialreac)vity•  Neuralapoptosis

Re)nalVasculopathy•  Microaneurysms•  Capillarynon-perfusion•  Neovasculariza)on

GeneralizedNeurodegenera)on•  Peripheralnerves•  Autonomicnervoussystem•  Brain

GeneralizedVasculopathy•  Renal•  Heart•  Brain

Diabetes

VebraakFD.NeuroreCnalDegeneraConinRelaConofVasculopathyinDiabetes.Diabetes2014;63:3590-3592.

Early Detection of Diabetes-Induced Retinal Vascular & Neural Dysfunction

n  Careful dilated fundus exam, including the periphery

n  OCT and OCTA n  Multi-spectral Imaging/FAF n  Widefield Retinal Imaging n  Macular pigment optical density n  ERG/VEP n  Contrast sensitvity n  Threshold Color Contrast Vision n  Threshold perimetry (FDT)

Retinal Vasculopathy

Retinal Neuropathy

Peripheral DR n  Predominantly peripheral diabetic

retinopathy lesions (PPL) significantly associated with increased non-perfusion, risk of progression and 50% more Hm/ma detected with UWF imaging than SSFP

n  DRCR.net Proocol AA is attempting to confirm the predictive value of PPL and association with other diabetes comorbidities

Ophthalmology. 2015 May;122(5):949-56

Ophthalmology. 2017 Jul;124(7):970-976 Ophthalmology. 2015 Dec;122(12):2465-72

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ImportanceoftheRe)nalPeripheryinDR

n  StudyatJoslinshowedthatpa)entswithpredominantlyperipheralDRlesions(PPL)weresignificantlymorelikelytoprogress(3.2X)anddevelopPDR(4.7X)p=0.005

n  Pa)entswithPPLhadsignificantlymoreischemiaonUWF

angiography

n  Comparedtostandardizedseven-fieldstereophotos(ETDRSstandard),UWFsuggestedamoreseverelevelofDRin10%ofcases

n  DRCR.netProtocolAAwillevaluatethepredic)vevalueofUWFimagingonocular/systemicendpoints(studycomple)onin2020)

Ophthalmology.2015May;122(5):949-56.

Ophthalmology.2015Dec;122(12):2465-72

Ophthalmology.2013Dec;120(12):2587-2595

UWF Imaging is avaialble from Eidon, Optos and Zeiss

ComparisonofOptosCalifornia&ZeissClarus500

n  46eyeswithasingleimagecapturen  GoodconsistencyregardingDRgradingn  Optosdeviceimagedameanof465DDversusamean243DDwithClarus(200vs133degrees)

n  85%ofOptosversus7%ofClarusimagesshowedobscuredareaswithinthe7ETDRSfields(p<0.001)

n  Noevalua)onofobservedareaoutsidethe7ETDRSfields

BMC Ophthalmol. 2018 Dec 20;18(1):332.

FAF imaging detects significantly more miroaneurysms than does standard

color photography (p < 0.016)

J Ophthalmol. 2016;2016:1287847

KeyPointforOptometry

•  DMEistheleaingcauseofvisionlossfromdiabetes– OCTisTHEBESTWAYtoiden)fyDME

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sdOCT is great for monitoring DME, response to therapy & detection of subclinicl DME

Up to 30% of DME is undetected by stereo funduscopy and these patients are 3X more likely to develop CSME Ophthalmologica. 2013;230(4):201-6.

OCTA n  Optical coherence tomography

angiography

n  64,000 squential B-scans/sec allows visualization of vascular perfusion

n  Fast, dye-less, no iatrogenic risk

n  Allows visualization of subclinical microaneurysm formation, capillary non-perfusion, neovascularization at the vitreoretinal interface

Curr Diab Rep. 2016 Dec;16(12):123 Retina. 2015 Nov;35(11):2364-70

PaCentwithT1DMx10years

20/15 Vision Minimal NPDR on clinical exam

Superficial capillary plexus Deep capillary plexus

OCTAshowsDRNOTseenonclinicalexam

OCTA Findings Linked to DR Progression

n  57 eyes with mild/moderate/severe NPDR and PDR

– retrospective analysis

n  Increased FAZ, and both decreased vessel density and flow area in the DCP were highly associated with worsening DR severity (p < 0.01) ARVO 2017

OCTA Identifies Pre-Clinical DR

n  Parafoveal vessel density in the choriocapillaris, superficial and deep capillary plexi of diabetes subjects is significantly reduced compared to controls

n  Density normals > DM sans DR > DM with DR

n  OCTA showed ma and nonperfusion in 11%/25% of patients without clinical DR

Acta Diabetol. 2018 May;55(5):469-477

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Re)nalDiabe)cNeuropathy(RDN):DetecCngNeuro-degeneraConwithOCT

OCTImaging•  Nervefiberlayer

•  Ganglioncelllayer

•  Innerplexiform•  Innernuclear

•  Outerplexiform•  Outernuclear

•  ExternallimiCng•  Photoreceptor

IS/OS•  ReCnalpigment

epithelium

ReCnaldiabeCcneuropathy(RDN)manifestsonopCcalcoherencetomographyassignificantthinningofthereCnalnervefiberlayerandganglioncellandinnerplexiformlayers

RiccaAM,SohnEH,AbramoffMD.NewThinkingOnDiabetesandtheReCna:TheProcessofReCnalNeurodegeneraConPrecedesMicrovascularDisease.15Nov2016.ReviewofOphthalmology.

Innerre)nalthinninginDiabetes

•  Innerre)nalthinning(bothganglioncell-IPLAKA‘ganglioncellcomplex’andRNFL)– “ReCnalDiabeCcNeuropathy”(RDN)– 4-10Xincreasedriskofcardiacautonomicneuropathy

– CANincreasesriskofMI,stroke,death2-3fold

PLoSOne.2017Mar23;12(3):e0174377.

CourtesyofA.PaulChous,ODOptometryTimesFebruary15,2017

Diabetes & RDN 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 & dark adaptation

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 InvestOphthalmolVisSci.2016Jan1;57(1):208-17.

ColorVisionDeficits•  40%ofDMpa)entswithnoophthalmoscopicallydetectablere)nopathyhaveacquiredcolorvisiondeficits

•  Selec)velossofS-conefunc)onpredominates– S-conepaucity&heightenedphototoxicity

ReCnopathyEpidemiologyandMolecularGeneCcsStudy(SNDREAMS-II,Report3).PanC-W,ed.PLoSONE.2015;10(6):e0129391

Chroma)cContrastThresholdisaMarkerofRDN

•  ChromaCcvisualdisturbanceinassociaConwithreCnaldiabeCcneuropathyprecedesclinicaldiabeCcreCnopathyin55%ofpaCents

•  55%-65%ofpa)entswithdiabe)cre)nopathyhavecolorvisiondefects

•  Blue-yellowdeficiencyisfoundinalmost90%ofpaCentswithdiabeCcreCnopathy

SilvermanSE,HartWH,GordonMO,KiloC.TheDyschromatopsiaofOpCcNeuriCsIsDeterminedinPartbytheFoveal/PerifovealDistribuConofVisualFieldDamage.InvestOphthalmolVisSci31:1895-1902,1990.

Computer-assistedextendedcolorvisiontesCngdeterminesthetypeofcolorvisiondefectandtheseverityof

thediabetes-induceddyschromatopsia

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T1DMx19yrs20/20OD20/20-1OSMild-moderatetritandefectOSñCRTAsymptoma)c

Chous Eye Care Associates

Licensed, developed, and produced under CRADA by Konan Medical USAin collaboration with the United States Air Force School of AerospaceMedicine OBVA (Operational Based Vision Assessment Laboratory).Copyright 2017. All rights reserved.

KonanMedical.com/ColorDx

nameVickie Saugen

test methodCCT HD (8bit)

scoring methodUSAFOBVA160701

ID test IDS | OD - OS

test date | time13 Dec 2017 | 14:16:40

age63

eye(s)OD, OS

app version0.1.92

genderFemale

distance2 feet

last calibration01 Sep 2017 | 10:10:17

PsiCone Threshold Trials

AveTime Score Category¹

OD Blue S 33.1% 30 6.4 68 Color Deficient (Tritan)

OS Blue S 75.0% 30 5.6 33 Color Deficient (Tritan)

¹Cut-off criteria are physician-selected from USAF, or user input score method ranges and corresponding assigned categories.

D A

T A

R E

S U

L T

S

Chous Eye Care Associates

Licensed, developed, and produced under CRADA by Konan Medical USAin collaboration with the United States Air Force School of AerospaceMedicine OBVA (Operational Based Vision Assessment Laboratory).Copyright 2017. All rights reserved.

KonanMedical.com/ColorDx

nameVickie Saugen

test methodCCT HD (8bit)

scoring methodUSAFOBVA160701

ID test IDS | OD - OS

test date | time13 Dec 2017 | 14:16:40

age63

eye(s)OD, OS

app version0.1.92

genderFemale

distance2 feet

last calibration01 Sep 2017 | 10:10:17

PsiCone Threshold Trials

AveTime Score Category¹

OD Blue S 33.1% 30 6.4 68 Color Deficient (Tritan)

OS Blue S 75.0% 30 5.6 33 Color Deficient (Tritan)

¹Cut-off criteria are physician-selected from USAF, or user input score method ranges and corresponding assigned categories.

D A

T A

R E

S U

L T

S

Full-FieldFlickerERGtoDxSevereDR•  DelayedimplicitCme(>36milliseconds)detectedanyDRandsevereNPDR/PDRwith84%and89%sensiCvity,respecCvelycomparedtoreCnalspecialistexam– 48controland118diabeteseyes(Japan)– Hand-heldnon-mydriaCcflickerERG

– Non-mydriaCcSciRep.2016Nov8;6:36591

RETevalERGisahand-helddevicethatmeasuresvisualfuncConusingafull-field

electroreCnogramtesCngprotocol Scien3ficReports,volume6,ArCclenumber:36591(2016)

OtherOD-FriendlyTests•  FrequencyDoublingPerimetryandContrastsensi)vityprogressivelydis)nguishDMandworseningDRfromage-matchedsubjectswithoutDM

•  MacularPigmentisreducedinpa)entswithDMandisinverselyassociatedwithDRseverity

•  SeveralRCTsshowthatcarotenoid+an)oxidantsupplementa)onimprovesvisualfunc)oninDMandDR

InvestOphthalmolVisSci.2017May1;58(6):BIO277-BIO290BiomedResInt.2013;2013:341269.BrJOphthalmol.2016Feb;100(2):227-34.

ReCna.2015Sep;35(9):1808-16InvestOphthalmolVisSci.2010Nov;51(11):5840-5

BrJOphthalmol.2016Feb;100(2):227-34.ReCna.2017Jul;37(7):1277-1286EyeVis(Lond).2017Oct15;4:23.

Macular Pigment •  MPOD is lower in patients with diabetes

and lower still in patients with increasing severity of DR

•  Macular pigment is inversely associated with visual function in many studies

•  ECPs should measure and optimize MPOD in our patients with and at-risk for diabetes

BrJNutr2009Jan;101(2):270-7.InvestOphthalmolVisSci.2010Nov;51(11):5840-5

Molecules.2017Apr20;22(4).pii:E610

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Treatment&ManagementGoals•  Delaythedevelopmentofdiabetes•  Delaythedevelopmentofdiabe)cre)nopathy•  ArrestorslowtheworseningofDR•  Referfortreatmentofsight-threateningdisease(PDR/Center-involvedDME)

KarlMarx-ThesesonFeuerbach,1845

IMPACT OF INTESIVE THERAPY OF DIABETES: Summary of Major Clinical Trials

Trial Microvascular

UKPDS

DCCT/EDIC*

ACCORD

ADVANCE

VADT

Initial Trial Long-Term Follow-up

*T1DM

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854 Holman RR et al. N Engl J Med. 2008;359:1577 DCCT Research Group. N. Engl J Med 1993;329:977 Nathan DM et al. N Engl J Med. 2005;353:2643 Gerstein HC e al. N Engl J Med. 2008; 358:2545 Duckworth W et al. N Engl J Med. 2009; 360;129

Ø  United Kingdon Prospective Diabetes Study Ø  Diabetes Control & Complication Trial Ø  Epidemiology of Diabetes Interventions &

Complications Ø  Action to Control Cardiovascular Risk in Diabetes Ø  Action in Diabetes and Vascular Disease Ø  Veterans Affairs Diabetes Trial

Metabolic Memory

Good Control Does NOT Eliminate Risk of Severe DR � 10 year risk of PDR and/or CSME

in a newly Dx patient with A1c = 6.5% and BP = 120/80 is nearly 4%

� With mild NPDR the 10 yr risk is 8.4%

Diabetologia. 2011 Oct;54(10):2525-32

BloodGlucoseReality

� Many patients never or rarely check their glucose

� Many patients never get A1c < 7% within the first 5 years - when tight glucose control is most effective at preventing DR

ARealityCheck

Hypoglycemiaisdisabling&canquicklyincapacitate(evenkill)pa)ents

Manypa)entsoptforchronichyperglycemiabecauseithasfarlessimpactonfunc)on,andtheconsequencesaredistantin)me

We must correct time myopia as well as refractive myopia

IsHbA1ctheBestPredictorofDRRisk?

•  Diseasedura)onandHbA1cthoughttobemostpredic)veYET….

•  AnalysisofDCCT/EDICdatashowsthatmeanA1cduringthestudiesaccountedforamere6-11%ofDRrisk!

•  Moreover,theJoslin“GoldMedlist”studyshowedli_lecorrela)onbetweendevelopmentofsight-threateningDRandA1cinpa)entswithT1DM>50years…….

Glacco et al. Diabetes. 2015 Sep;64(9):3273-84

DiabetesCare.2011Apr;34(4):968–974

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WhyHbA1cIsn’ttheWholeStory•  Doesn’treflectglucosevariabilityortheburdenofacutehypoglycemia

•  USspent$1.25billionin2009onhospitalizaConsforseverehypoglycemia

JMedEcon.2016Sep;19(9):852-7.

GlucoseSpikesIncreaseDRRisk

•  T1DMpaCents>10years(n=23)

•  ConCnuousglucosemonitoring(DexCom)showedsameA1cbutdramaCcincreaseinglucosespikes>400mg/dlinsubjectswithmoderate-severeNPDR(nodifferenceif>350or250)– 1spike/2.6daysinthosewithNPDR– 1spike/9.9dayinthosewithout

ARVOMay7,2017

The Perils of Transient Hyperglycemia n  A 6 hour episode of elevated glucose (> 190

mgd/l) results in a 6-day massive increase in mitochondrial reactive oxygen species AFTER blood glucose is totally normalized

• High ROS persist for 2 weeks before normalizing

n  ROS are the driving force underlying DR

n  These glycemic exursions are often too short to be captured by mean glycemia (HbA1c)

Diabetes. 2015 Sep;64(9):3273-84.

Pathophysiology n  Blood vessel damage in diabetes

is mediated by four distinct biochemical pathways driven by mitochondrial production of ROS

Intracellular Glucose & FFAs

mitochondria

ATP + éSuperoxide (O2-)

Mitochondrian

The Four Pathways

n  Polyol n  Hexosamine n  Protein Kinase C (PKC) n  Advanced Glycation Endproducts

(AGEs)

Each of these pathways depends on over-production of reactive oxygen

species (O2-) by mitochondria exposed

to excess glucose and/or free fatty acids

DR Glucose Metabolism

Glucose

Glucose-6-phosphate

Fructose-6-phosphate

Glyceraldehyde-3-phosphate

1,3 Diphosphoglycerate (harmless metabolite)

GAPDH

Polyol Pathway

Hexosamine Flux

Protein Kinase C Advanced Glycation Endproducts

ROS

ATP +

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Post-Prandial Hyperglycemia •  So what do we do? •  More research needed in humans

•  Optimize HbA1c

•  Try to minimize duration of episodic hyperglycemia > 190 that may be too brief to be captured by HbA1c

•  Minimize blood glucose spikes > 400 •  Increase the glucose time-in-range

A10-minutewalkagertheeveningmealloweredglucose22%morethana30-minutewalkbeforeanymeal

Diabetologia2016;59December2016,Volume59(12):2972-78FIASP

Techniques

CGMUpdates

• ConCnuousglucosemonitoringsystems

•  Constantbiofeedbackregardingcurrentbloodglucoseandtrend

•  CMSrequiresinsulinuseandintensiveglucosemanagementwith4homebloodgluose•  Measurements/day

CGM&TIR•  Con)nuousglucosemonitoring(CGM)systemscapturereal-)medataandallowmeasurementofglucose)me-in-range(TIR)– <70,70-180,>180mg/l– DexComClarity&MedtronicSugarIQappsmeasuresTIRintandemwiththeirCGMs

•  A10%decreaseofTIRresultsina61%increasedriskofre)nopathyincidence&2-stepETDRSprogression–  Post-hocanalysisof7-pointDCCTfingers)ckdataBeyondHbA1cindiabetes:itisCmetolookatotheroutcomes;ADAScienCficSessions-June24,2018,Orlando,FL

Prac)calImplica)onsofTIR

•  ModerateNPDRT1DMx10years•  HbA1c=7% TIR=60%(14.4hours)

•  Toachievea40%reduc)oninriskofprogressingtoSTDR,hecould:

– ReduceHbA1cto4.1%– IncreaseTIRto73.6%(17.6hours)

Source:www.Re)naRisk.com

BiggestBenefitWhenHbA1cIsAlreadyLowerandTIRisalsoLOW

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MedtronicSugarIQPredicCveReponseApp

+36minutesTIR

.Real-worldassessmentofSugar.IQwithWatson—AcogniCvecompuCng-baseddiabetesmanagementsoluCon(16-OR).Presentedat:AmericanDiabetesAssociaCon78thScienCficSessionsinOrlando,Florida,June22-26,2018,inOrlando,Florida

FDA-approvedPseudo-ClosedLoopAvailablein2018

Medtronic670G

VinegarBa_lesGlucoseSpikes

n  VinegarimprovesinsulinsensiCvityinIRsubjectsDiabetesCare.2004Jan;27(1):281-2

n  2Tbspvinegarconsumedbeforea75gCHOmealpreventedpost-prandialglucosespikesinptswithT1DMandreducedAUCBGby20%•  AceCcaciddelaysgastricemptyingandenhancesglycogenrepleCon

Diabetes Care. 2010 Feb;33(2):e27

Super-fast-Ac)ngInsulins

•  Fiasp–fast-acCnginsulinaspart(NovologwithniacinamideadjuvantformsinsulinmonomertopenetrateSCfatmorerapidly)

•  29point1-hourreducConinpost-prandialglucose;12pointreducConat2hours

•  0.15%dropinHbA1c

•  UKstudyes)mates1%dropindiabetes-relatedblindnessand1715poundsavingsperpa)ent

DiabetesTechnolTher.2017Jan1;19(1):25–33

DiabetesObesMetab.2017Jun1.

AvailableinUSMarch2018

Fast-AcCngInsulinAspart•  MonomericAspart(Novolog,NovoNordisk)•  MuchmorerapidonsetofacCon

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Fenofibrate – oral therapy to prevent progression of DR

n  Approved first-line therapy for mild-moderate NPDR in Australian adults with T2DM

NNT = 14 for prevention of CSME or PDR

n  Fenofibrate significantly decreases muliple inflammatory cytokines in patients with DR (VEGF, IL1B, LpPLA2)

Ophthalmic Epidemiol. 2014 Oct;21(5):307-17

Medicine(BalCmore).2017Aug;96(31):e7671.

BrimonodineandSomatosta)nRetardNeurodegenera)on

•  BIDcombinaConeyedropin700+withT2DMfollowedfo2yearsv.placebo(EuroCondorTrial)

•  ThosewithmulCfocalelectroreCnogramabnormaliCesatbaselinehadlessevidenceofneurodegeneraConbymfERG(p<0.01)

Diabetes.2017Sep;66(9):2503-2510.

EuroCondorResearchGroup

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

n  With and without retinopathy

n  Daily use of a novel, multi-component nutritional supplement

n  CSF, MPOD, color vis., macular perimetry, OCT, A1c, lipids, 25(OH) vit. D, TNF-a, hsCRP, DPNS score

Diabetes Visual Function Supplement

Study (DiVFuSS)

BrJOphthalmol.2016Feb;100(2):227-34

Test Formula � Zeaxanthin & Lutein � Benfotiamine � Alpha Lipoic Acid � Vitamin D � Vitamins C & E � Mixed Tocopherols/

Tocotrienols � Resveratrol � Green Tea

� Curcuminoids � N-Acetyl Cysteine � Grape Seed Extract � CoQ10 � Zinc Oxide � EPA/DHA � Pycnogenol � Vitamin B12

Mean Change/SD in visual function measures, serum lipids, hsCRP, TNF-α, glycohemoglobin, foveal thickness and symptoms of diabetic peripheral neuropathy with 95% p-Values

Δ from baseline Suppl v. Plac p-Value

Color Error Score -20.55+24.37 +7.5+22.01 <0.0002

5-2 MD (db) +2.78+9.83 -0.75+0.98 <0.0001 MPOD (du) +0.09+0.05 -0.01+0.03 < 0.0001 LDL-C (mg/dl) -7.61+16.08 +0.82+10.15 0.01 HDL-C (mg/dl) +3.82+6.24 -1.61+5.31 0.0004 TGs (mg/dl) -10.46+28.48 +2.39 +11.56 0.01

hsCRP (mg/L) -2.14+3 -0.28+1.83 0.01 TNF-a (pg/ml) +0.78+5.04 +0.56+2.79 0.88

HbA1c (%) -0.1+0.4 +0.1+0.4 0.06

Foveal Thickness 2.66+11.25µm 0.34+3.48 µm 0.35

DPNSS -30.7% +10.7% 0.0024 Fisher’s Exact Test

Animal model of DR •  DiVFuSS formula prevents mtDNA damage,

normalizes ROS and VEGF, and prevents retinal capillary apoptosis

13.4

kb:2

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40

80

120

Nor Diab C-AO

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#

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100

150

200

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Nutr Metab (Lond). 2014 Jan 30;11(1):8.

VEG

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0.5

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1.5

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VEGF

Meanglucoseofstudyanimals=1100mg/dl

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Long-ChainOmega-3PUFA

•  PrediMedTrialcomparingMediterranean-typedietsupplementedwithextravirginoliveoilortreenutsversusAHAdietagainstCVeventsinpaCentswithT2DM(n-3482)

•  PrimarytrialhaltedearlybecausebothMeddietsweresignificantlysuperior,especiallyforstrokeprevenCon

•  Subjectsconsuming>500mgdailylong-chain-ω3PUFAwere48%lesslikelytodevelopSTRover6yrscomparedtothoseconsuming<500mg(p=0.001)

JAMAOphthalmol.2016Oct1;134(10):1142-1149

HowFarOutoftheBarnMusttheHorseBetoStartTreatment?

Evidence-basedTipsforMinimizingDiabe)cRe)nopathy

•  Don’tgetdiabetes/Don’tgetprediabetes•  GetHbA1caslowassafelypossibleaquicklyaspossiblea~erDx;keepBP<140/90

•  Limitpost-prandialhyperglycemia<5hours•  Consumeatleast500mgLCω3PUFA/day•  Increasefiber&macularpigment•  Considerascience-basednutriConalsupplementforDR

PrevalenceofDRintheUS

1.  NHANES2005-2008,projectedto2012USpopulaCon.2.  CentersforDiseaseControlandPrevenCon.www.cdc.gov.AccessedJune9,2014.SaaddineJB,etal.ArchOphthalmol.2008;126(12):1740-1747.

3.  BioTrendsResearchGroup.TreatmentTrends®:DiabeCcReCnopathy/DiabeCcMacularEdema(US)2013.4.  ProprietaryQuanCtaCveMarketResearch(n=103reCnaspecialists,n=23,994DMEeyeswithcentralinvolvement);fieldedNovember2013.

Approximately 8 million (26%) of people with diabetes have DR1 •  5.8 million are diagnosed1-3

•  2.3 million have DME3

DRPrevalence DRDiagnosed DMEPrevalence

DMEDiagnosed

DMETreatedDMEAnC-VEGFTreated

8.0MM1

1.5MM3 2.3MM3

5.8MM1-3

≈400K4 ≈240K4

2.2MillionwDRUNDIAGNOSED800,000wDMEUNDIAGNOSED

WhentoRefer?•  Itdependsonyourcomfortlevel

• MyAnswer:– Whenthepa)entneedstreatmentofDR/DME

– WithunexplainedVAloss– WhenIamunsureofthediagnosis

– Whenthepa)enthaschronic,sub-op)malmetaboliccontrolorisreceivingdecidedlysub-op)malcare;frequenthypoglycemia;kids

Sight-threateningDR–MustRefer

PDR CI-DME

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RiskforProgressingtoPDRin1yr

� MildNPDR:5%� ModerateNPDR:12%� SevereNPDR:52%� VerySevereNPDR72%

Itiskeytoiden)fypa)entswithsevereNPDRforreferral

ETDRS: Early Treatment Diabetic Retinopathy Study� WhentoWorryAboutNPDR• WhenthereisassociatedDME

• WhenitqualifiesasSevereNPDR– The4-2-1Rule– Hmg/MA– VenousBeading– IRMA

Per ETDRS

An)-VEGFTherapyforNPDR•  Lucen)sisnowapprovedtotreatanylevelofDRwithorwithoutDME

•  Eyleaisexpectedtoreceivesimilarapproval

•  SignificantimprovementsinDRseverity,especiallyinthosewithmoderatelysevereorworseNPDR(DRSSLevel47+)

• ETDRSseveritylevel47:mul)pleintra-re)nalhemorrhagesintwoormorequadrants,anyveinbeading,anyprominentIRMA

DiabeCcReCnopathySeverityScore(DRSS)Exampleof2-StepImprovement

SevereNPDRDRSSLevel53(Level6)

ModerateNPDRDRSSLevel43(Level4)

•  SeverereCnalhemorrhagesin4quadrants,or

•  Venousbeadingin≥2quadrants,or•  ModeratelysevereintrareCnal

microvascularabnormaliCes(IRMAs)in≥1quadrant

•  Microaneurysms,plus•  MildIRMAs,or•  ModeratereCnalhemorrhages

ALLHADDME

PANORAMAPhase352WeekData

•  Aflibercept(Eylea)Q8orQ16weeksformoderatelyseveretosevereNPDRsansDME

•  80%/65%achieved2-stepDRSSimprovement– p<0.0001

•  VTC(PDR/ASneo)reduced82-85%•  CI-DMEreduced68-74%

RegeneronPressStatement,October25,2018

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WhysomepeoplewithDRareLosttoFollow-up(LTFU)

•  AstudyfromSanFranciscolookedatriskfornon-compliance

•  209paCentsmeanage58yowA1c8.5•  46%ofpaCentsa]ended<80%off/u•  Riskfactorsformissingf/u:

– FootinvolvementOR2.4– Foot/kidneyOR3.7– MajordepressivedisorderOR2.1– MediCalorSFHealthinsurance.OR5.01/6.79

Chenetal.CompliancewithDRf/u.Ophthal.Epidemiol.8/18.

EmergingTreatmentsforDR/DME

•  CombinedAn)-VEGF&Angiopoe)n-2Blockade–>Farcimab™

•  TyrosineKinase(TIE-2)Ac)va)on– Subcutaneousinjec)onimprovesDRandDKD– AerpioTherapeu)cs

•  Adenoviral-AssociatedVectorGeneTherapy– Intrvitreal– Sub-RPE

Ac)vatedTie-2promotesvascularstabilityTyrosineProteinKinaseReceptor VEGF+ANG-2Blockade-RESULTS

FarcimabcomparedtoLucen)s:-3.6morele_ersgained-Moregain1+to3+lines-Morehavea>2stepDRSSimprovementAT24WEEKS

SubcutaneousTIE-2AcCvator•  TIME-2bstudy•  AerpioTherapeuCcsAKB-9778•  167subjectswithmoderatetosevereNPDR•  1or2subcutaneousinjecCons/day

•  EarlydatashowsimprovementofDRseverityandrenalfuncCon:studycompleCon06/2019

Be]erThan

ReCnalPhysician,July2017

SubcutaneousInjec)onforDR

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PharmacolTher.2017May;173:1-18

Adenoviral-AssociatedVectorGeneTherapyProducesAflibercept KeyPoints•  Diabetescausesbothvascularandneuronaldamagewithinthere)na

•  Mul)pletechnologiescanhelpusdetectboth

•  WECANDOMOREthansimplymonitorpa)entsforthedevelopmentofsight-threateningre)nopathy

•  TherapiesforadvancedDRsavevision

•  Preven)ngdiabetesisthebestwaytopreventocularcomplica)ons

Evidence-Based Tips To Avoid Diabetes n  Exercise 30 minutes each day (soon after waking) &

minimize added sugars n  Eat a predominantly plant based diet including a variety

of fruits and vegetables and more vegetables n  Minimize processed meats n  Drink coffee or tea n  Sleep > 6 hours per night and < 9 hours n  Get your serum vitamin D > 40 ng/ml n  Don’t smoke n  Live away from smog n  Breast Feed n  Turn down the thermostat n  Reduce Light at Night n  Fast if you’re obese

Am J Med. 2013 Jul;126(7):583-9

2014 US Surgeon General’s Report

Am J Med. 2013 Jul;126(7):583-9

Am J Med. 2013 Jul;126(7):583-9 Am J Med. 2013 Jul;126(7):583-9

Am J Med. 2013 Jul;126(7):583-9

Sleep Med Rev. 2015 Oct 21;30:11-24 PLoS One. 2015; 10(11): e0141724.

Curr Nutr Rep. 2014 Dec 1; 3(4): 364–378. Environ Health Perspect. 2015 May; 123(5): 381–389

ReversingT2DM

Patient PK

n 52yomale-T2DMx2years–noDRn Me}ormin+Januvia®(sitaglip)n)

n A1c6.6%atDx,loweredonmedsbutnow7.4%andplacedoninsulin(Lantus®)QHS

n  BMI38atDxandnow40kg/m2

n Wediscussedop)ons,includingalternatedailyfas)ng(ADF)combinedwithPaleo-typelowcarbdieton‘feedingdays’

PK6monthslatern 35lbsweightloss(BMI=30Kg/m2)

n A1cnow5.4%andhasdiscon)nuedinsulinandJanuvia

n PKreportsincreasedenergy,libidoandclearerthinking

n “ThiswasthebestthingI’veeverdone”

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Why ODs Should Be on The Diabetes Care Team

n  We are often gate keepers into the health care system for many patients

n  Diabetes and diabetic retinopathy are largely preventable conditions and ODs do a fabulous job educating our patients

n  DM an DR cases continue to climb

n  Our countries, communities, other HCPs and patients need us

ThankYou!