new fron)ers in the financial disclosures detec)on ......2/28/19 1 new fron)ers in the detec)on...
TRANSCRIPT
2/28/19
1
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
2/28/19
2
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
2/28/19
3
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
2/28/19
4
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
2/28/19
5
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
2/28/19
6
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
2/28/19
7
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
2/28/19
8
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
2/28/19
9
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 +
2/28/19
10
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
2/28/19
11
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
2/28/19
12
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
10bp
0
40
80
120
Nor Diab C-AO
*
#
mtDNA damage
Tota
l RO
S (%
nor
mal
)
0
50
100
150
200
250
Nor Diab C-AO
*
#
oxidative stress
TUN
EL+
capi
llary
cel
ls/re
tina
0
5
10
15
20
Nor Diab C-AO
*
#
capillary cell apoptosis
Nutr Metab (Lond). 2014 Jan 30;11(1):8.
VEG
F (p
mol
/ug)
0.0
0.5
1.0
1.5
2.0
Nor Diab C-AO
*
#
VEGF
Meanglucoseofstudyanimals=1100mg/dl
2/28/19
13
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
2/28/19
14
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
2/28/19
15
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
2/28/19
16
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”
2/28/19
17
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!