1. A. Paul Chous, MA, OD, FAAO. Tacoma, WA. Diabetic Eye Disease: ....
hypercoaguability (↑PAI-1) ... 386 mg/dl. 65 mg/dl. 101 mg/dl. 136 mg/dl. 350 mg
/dl. 314 mg/dl. 12%. 8%. 279 mg/ ..... Endothelial Shear Stress = RPP x Resistivity
Index.
Disclosures
Diabetic Eye Disease: Biochemistry, Ocular Hemodynamics & Some New Strategies For Prevention
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
A. Paul Chous, MA, OD, FAAO
None of these affiliations have affected the content of this presentation
Tacoma, WA
Why Should We Care About This Topic?
Why We Should Care
After all……
Laser photocoagulation is highly effective at reducing severe vision loss from diabetic retinopathy Tight metabolic control of diabetes significantly reduces risk
loss, poor night vision)
Diabetes – A “Growth Industry”
Prevalence
Optometrists care for the eyes of the majority of Americans with diabetes Most people with diabetes have suboptimal metabolic control Some people with good metabolic control still develop severe DR Diabetes is a “Growth Industry”
Metabolic Control in US Diabetes Patients
> 50% have A1c > 7%
J Clin Hypertens 2010 Oct;12(10):826-32.
27 Million Americans 1.8 million with type 1 diabetes 18.5 million with type 2 diabetes 9 million undiagnosed
Incidence
1.9 million new cases annually (US)
Photocoagulation doesn’t always work & has significant functional sequellae (VF
Per AACE guidelines, half of patients with T2DM are on inappropriate meds Arch Intern Med. 2008 Oct 27;168(19):2088-94
Up to 70% of patients with diabetes have blood pressure levels above target J Gen Intern Med. 2008 May;23(5):588-94
1
Epidemiology of Diabetes
By 2030
190 million cases world wide; 333 million by 2020 (WHO) 79 million Americans have “prediabetes” Impaired Fasting Glucose and/or
500,000,000 People Will Have Diabetes
Impaired Glucose Tolerance
IDF 2013 State of Diabetes Report
US Healthcare Costs Attributable to Diabetes, 2012
Good Control Does NOT Eliminate Risk of Severe DR
For Patients of All Ages: Total = $245 Billion Drugs $50 billion
Hospital inpatient days $98 billion
Outpatient care* $58 billion Nursing home days $39 billion
Estimated that by 2020 1/3 of US healthcare dollars will be spent on diabetes
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
American Diabetes Association. Diabetes Care. 2008 Mar;31(3):596-615.
Patient JK – 62 yo male Dx with
T2DM x 6 years and A1c < 6.2% and BP < 125/84 since diagnosis
DR – some real numbers
Pooled analysis from almost 23k with DM • • • •
34.6% prevalence for any DR 6.96% for PDR 6.81% for DME 10.2% for Vision Threatening DR (PDR and/or DME) • All DR end points increased with DM duration, A1c & BP Higher in people with T1DM compared w T2DM
Worldwide: 93M w DR, 17M PDR, 21M DME, 28M VTDR
Yao et al. Prevalence of DR. Diabetes Care . March 2012
2
Other Ocular Diseases More Common in Diabetes
Cataract Glaucoma Dry Eye & Keratopathy Efferent Cranial Neuropathy Ischemic Optic Neuropathy Retinal Vascular Occlusion
Pathophysiology
Most Diabetes Complications Can Be Broadly Classified as Affecting Small Blood Vessels (Microvascular) or Large Blood Vessels (Macrovascular)
Complications
Diabetes is the Sixth Leading Cause of Death in the US (estimates range from 100-400 thousand/yr) due to cardiovascular and cerebrovascular disease Based on CDC estimates, diabetes complications kill five times as many Americans each year as do AIDS and breast cancer combined
Basic Biochemistry of Diabetes Complications
Many complications share the same underlying biochemistry Glucose Molecule
Diabetes Causes Multiple Metabolic Abnormalities
Hyperglycemia (IR and/or loss of beta cells)
Dyslipidemia (small, dense LDL & sticky platelets)
Hypertension (stiff vessels, sludgy blood) Increased Formation of Reactive Oxygen Species (ROS)
•Some tissue and cell types are insulin independent •Retina •Renal Glomeruli GLUT-4 •Aorta •Neuronal microvessels This makes these sites susceptible to hyperglycemic insult
3
Insulin Resistance and Hyperglycemia are Associated with Dyslipidemia & Endothelial Dysfunction
Macrovascular Complications of Diabetes
Elevated triglycerides, CRP, LDL & FFAs Increased CAMs (ICAM-1) increase leukocyte adhesion to vessel walls Glycation of LDL particles makes them smaller & denser (ie more atherogenic) Increased platelet aggregation and decreased fibrinolysis causes a state of hypercoaguability (hPAI-1)
Oxidative Stress
Endothelial Dysfunction
Pathophysiology
Coronary Artery Disease Cerebrovascular Disease Peripheral Vascular Disease
Hypercoaguability Vasoconstriction Inflammation
Ocular Sequellae with Shared Mechanism: Retinal Vascular Occlusion NAION Diabetic Retinopathy
Disease
Fatty Acid Oxidation in Macrovascular Disease
Macrovascular Insult
Mitigating Macrovascular Insult (ADA 2014 Standards)
Treat dyslipidemia – Glycemic control, statins, ASA
Physical activity & dietary modification – Decrease insulin resistance and hyperinsulinemia – Weight loss to decrease VAT stores
Tighten glycemic control – Minimize glycation of LDL-C & vessel walls
Source: Diabetes: American Diabetes Association, 2005
Lower blood pressure
4
Pathophysiology Microvascular Complications of Diabetes
Microvascular Insult Retinopathy Nephropathy Neuropathy Four biochemical pathways:
polyol, AGE, hexosamine, PKC
Pathophysiology
Glucose Metabolism
Blood vessel damage in diabetes is caused by four distinct biochemical pathways driven by mitochondrial production of ROS
Glucose Glucose-6-phosphate Fructose-6-phosphate
Intracellular Glucose & FFAs
Glyceraldehyde-3-phosphate GAPDH
mitochondria ATP + hSuperoxide (O2-)
Lactate
Glucose Metabolism
1,3 Diphosphoglycerate
Mitochondrian
Any increase in glucose concentration or decrease in GAPDH results in accumulation of these intermediate glucose metabolites These intermediate metabolites drive production of injurious compounds
Glucose Metabolism Glucose
Pyruvate & ATP
ROS
Polyol Pathway
Glucose-6-phosphate Fructose-6-phosphate Glyceraldehyde-3-phosphate GAPDH 1,3 Diphosphoglycerate
Hexosamine Flux Protein Kinase C Advanced Glycation Endproducts
(harmless metabolite)
5
AGEs and PKC
AGEs- The Maillard Reaction
Strongly implicated in DR AGEs = advanced glycation endproducts – Irreversible glucose-protein bonds – Play a role in retinopathy, nephropathy, neuropathy, CVD, Alzheimer’s
PKC = protein kinase C – Damages blood-retinal barrier – Recruits VEGF
Diabetes Diagnosis in the ECP’s Office
Measurement of fluorescence (AGEs) in the lens is a biomarker of long-term glycemic stress • The ClearPath DS-120 is designed for early detection of DM by patient comparison with age-matched norms (Freedom-Meditech)
Glycemic Variability
• Superior accuracy to blood tests • FDA clearance 2/2013
Blood glucose fluctuation generates more ROS than does static hyperglycemia Larger “glycemic excursions”
hO2-
Glycemic variability induces apoptosis of retinal capillary endothelial cells by up-regulating NF-kappa b
Journal of Diabetes Science and Technology, November 2012
Glycosylated Hemoglobin (%) vs. Mean Plasma Glucose (mg/dl) 13% 12% 11% 10% 9% 8% 7% 6% 5% 4%
Excellent
386 mg/dl 350 mg/dl 314 mg/dl 279 mg/dl 243 mg/dl 208 mg/dl 172 mg/dl 136 mg/dl 101 mg/dl Control 65 mg/dl
HbA1C
HbA1C is directly correlated to blood sugar averages, but says nothing about the consistency or stability of glycemic control 136, 132, 140, 135, 137
a HbA1C = 6.0%
48, 204, 240, 32, 87, 205
a HbA1C = 6.0%
6
Glycemic Variability in the DCCT
Intensively managed patients had a 50-60% reduced risk for developing DR compared with conventionally managed patients having identical HbA1c values After 14 years of follow-up (EDIC), there was a 58% reduced risk of major cardiovascular events in the intensive group after controlling for HbA1c
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
Is There Anything More We Can Do?
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 if and when necessary
What Causes Diabetic Retinopathy? • A number of complex and inter-related biochemical and hemodynamic factors – – – – – – – – –
Hyperglycemia Hypertension Inflammatory Dyslipidemia Oxidative Stress Release and Suppression of Growth Factors Hormonal influences Apoptosis Up-regulation of inflammatory cytokines BRB breakdown and hypoxia
7
Diabetes Hypertension
Growth Factors TGF PDGF IGF VEGF
BDNF PEDF
RAAS AGEs ET-1
Dyslipidemia
Atherogenic LDL
Hyperglycemia
Hormones
Cortisol GH
Mitochondrial ROS
AGEs
Hexosamine
PKC
Polyol
Can we use medical or nutritional therapies to bite the hands that Feed Diabetic Retinopathy?
Oxidative Stress
1. Blood Glucose Medications 2. Blood Pressure Medications
Apoptosis
Inflammation
RGCs/Inner Retina Capillary Endothelium
NFkB TNF-a, IL-6, MMP, kallikrein, ICAM
3. Meds for dyslipidemia
Diabetic Retinopathy BRB Breakdown Hypoxia/Neovascularization
ACEIs/ARBs & Retinopathy
Blood Glucose Control
Vasotec® (enalapril) and Cozaar® (losartan) reduced the risk of DR progression by 65% and 70% in T1DM NEJM 2009;361: 40-51
Meta-analysis of the DCCT and UKPDS shows that:
Captopril reduces DR progression 40% and DME 30% in T2DM Chin Med J (Engl) 2012 Jan;125(2):287-92
Each 10% Reduction in HbA1C Lowers the Risk of DRT Progression By 43%
Should these agents become standard treatment of DR?
This linear reduction in risk holds for HbA1C between 5% and 8%
-prils and –sartans may lower DR Risk of Progression
Drugs. 2010 Dec 3;70(17):2229-45.
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) ACCORD Eye Study, N Engl J Med. 2010 Jul 15;363(3):233-44 Consistent with FIELD Study showing reduced progression of DR and need for laser Tx
Biting the Hands of DR Might Also Entail Strategies That:
Reduce ROS and harmful glucose metabolites (AGEs, PKC, Polyol, hexosamine)
Reduce nfKB ‘switch’ that activates inflammation
Reduce inflammatory cytokines
Reduce/Block VEGF/TGF and augment BDNF/PEDF
Prevent capillary/pericyte/RGC apoptosis
Seal leaky retinal capillaries
Lancet 2007 370(9600):687-97
Add-on Fenofibrate lowers risk of DR progression in T2DM
8
Lutein & Zeaxanthin
Micro-Nutrient Candidates? Mitochondrial anti-oxidants, block nf-Kb, reduce Harmful glucose metabolites, inhibit lipid peroxides
Lutein & Zeaxanthin Vitamin D Resveratrol Curcumin EPA/DHA Coenzyme Q-10 Quercetin Green Tea Extract
Benfotiamine Pycnogenol Alpha Lipoic Acid Green Tea Extract Grape Seed Extract Acetyl-L Carnitine Vitamin C Tocotrienols
Higher serum ratio of L/Z to B-carotene associated with a 2/3 lower risk of any DR
MPOD is lower in diabetes and lower still in DR
L/Z supplementation increased MPOD and improved VA ,contrast and foveal thickness in NPDR patients
Lutein reduces nfKB & increases BDNF Zeaxanthin reduces VEGF and ICAM-1
Int J Ophthalmol 2011;4(3):303-6 Br J Nutr 2009 Jan;101(2):270-7.
Vitamin D
Exp Biol Med 2011 Sep 1;236(9):1051-63. Invest Ophthalmol Vis Sci 2008 Apr;49(4):1645-51
Curcumin
Vitamin D deficiency and insufficiency are associated with diabetes and retinopathy in both T1DM and T2DM Retinopathy severity is associated with worsening serum vitamin D status in T2DM
DR rates are lowest in India after all adjustments
High dose prevents DR in animals Lowers nfKB, VEGF, TGF-B, AGEs and pancreatic beta-amyloid
Down-regulates nfKB, TNF-a & inhibits neovascularization independently of VEGF Inhibits foam cell formation
Lancet 2010;376:124-36 Nutr Metab 2007 Apr 16;4:8.
.Endocr
Pract 2012 Mar-Apr;18(2):185-93
Diabetes Care 2011 Jun;34(6):1400-2
J Immunol
2012 Mar 1;188(5):2127-35
Pycnogenol
Diabetes Res Clin Pract. 2008 May;80(2):185-91
Clin Biochem 2000 Feb;33(1):47-51
Benfotiamine
30+ RCTs showing health benefits, including 4 showing lower A1c, oxidized LDL-C & BP Reduced retinal edema & improved blood flow in NPDR J Ocu Pharmacol Ther. 2009;25(6):537-40
Normalized activity in polyol, hexosamine, AGE, pathways in T1DM Diabetologia. 2008 Oct;51(10): 1930-2
Inhibits nfKB, VEGF Inhibits ACE/eNOS to lower BP Inhibits MMP-9 to reduce capillary leakage Lowers post-prandial glucose spikes
Totally prevented diabetic retinopathy in an animal model Normalized 4 major pathways of biochemical insult due to hyperglycemia (polyol, PKC, hexosamine, AGE) Blocks pericyte apoptosis due to hyperglycemia
Nat Med. 2003 Mar;9(3): 294-9 Inflamm. 2006 Jan 27;3:1)
J Ethnopharmacol. 2011
Jan 27;133(2):261-77
Diabetes Metab Res Rev. 2009 Oct;25(7):647-56
9
Diabetes Visual Function Supplement Study “It may be time to develop, test and educate ECPs & the public about an AREDS 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
(DiVFuSS)
6 month placebo-controlled RCCT of adults with T1DM or T2DM > 5 years With and without retinopathy Daily use of a multi-component nutritional supplement (lutein, zeaxanthin, D, C, E, Zn, curcumin, benfotiamine, Pycnogenol, lipoic acid, NAC, resveratrol, grapeseed extract, green tea, O-3 FAs, CoQ10)
CSF, MPOD, color vis., macular perimetry, OCT, A1c, lipids, 25(OH) vit. D, TNF-a, hsCRP, DNS score ClinicalTrials.gov Identifier: NCT01646047
Animal Model of DR
Supplementation with Test Formula prevented diabetes-induced increase in
• Test formula blocked early mitochondrial damage in rats
VEGF
NF-kB 250
VEGF (pmol/ug)
*
1.5
• Test formula blocked retinal capillary apoptosis underlying DR • Test formula improved b-wave ERG (retinal function) Kowluru RA – Kresge Eye Institute Presented at ARVO 2013, Seattle
#
1.0 0.5 0.0
Nor
Diab
C-AO
NF-kB-p65 (% normal)
2.0
*
200 150 #
100 50 0
Nor
Diab
C-AO
Kowluru RA – Kresge Eye Institute Presented at ARVO 2013, Seattle
dysfunction
capillary cell apoptosis
150 #
100
*
0
Nor
Diab
C-AO
oxidative stress 250
*
15 10 #
5 0
Nor
Diab
C-AO
mtDNA damage
200 150 #
100
So Will This Formula Work in Humans with Diabetes Mellitus?
120
*
13.4kb:210bp
Total ROS (% normal)
20
+
50
TUNEL capillary cells/retina
b wave ampl (25000mcd.s/m^2)
Supplementation with Test Formula prevented diabetes-induced retinal
#
80
*
40
50 0
Nor
Diab
C-AO
0
Nor
Diab
C-AO
10
Subject Characteristics (n = 55)
DiVFuSS Enrollment
55 total enrolled to date
31-79 yo (mean = 56 yrs)
29 with NPDR 26 with no DR 21 T1DM 34 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%
34 have completed the trial
Unmasked data recently analyzed for presentation at 2013 Academy of Optometry meeting
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
Relative Values of Serum Lab Markers Pre- (solid) and Post- (dashed) Supplemented Group in Black Placebo Group in Red
Unmasked Data (n = 34)
22 on active supplement (S)
6 T1DM/16 T2DM 10 DR/12 no DR mean duration = 22.6 yrs mean BMI = 30.04
12 on placebo (P)
2 T1DM/10 T2DM 7 DR/ 5 no DR mean duration = 21.8 yrs mean BMI = 32.7 HbA1c
No statistically significant differences at baseline between S and P groups
Color Error Score Right
Left
5-2 MD Right
T Chol
LDL-C
HDL-C
TGs
hsCRP
Mean Contrast For S and P Groups Pre- and Post Trial
Relative Measures of Visual Function and NFL Thickness Pre- (solid) and Post- (dashed) Supplemented Group in Black Placebo Group in Red
MPOD
25-OH D
Left
OCT Right
Left
11
Summary of Early Findings in Human Subjects
Though improved metabolic control
has a major impact on incidence of DR, many patients do not achieve this goal
DiVFuSS formula significantly improved visual function, including contrast sensitivity, visual field sensitivity and color perception
Targeting the pathways that drive
DR with science-based supplements makes biologic sense and requires more investigation
p = 0.002 to 0.05
DiVFuSS formula significantly reduced hsCRP p = 0.04
Blood Pressure Matters in DR – the UKPDS
The Hemodynamics of Diabetic Retinopathy
Designed to answer two questions: 1. Does tight glycemic control benefit Type 2 patients? 2. To what extent does blood pressure control influence outcomes?
UKPDS Conclusions
UKPDS Results – Blood Pressure
Mean BP of Intensive Group = 144/82 Mean BP of Conventional Group = 154/87
Complication
Worsening Retinopathy Severe Reduction in Vision Death Caused by Diabetes Stroke
Reduction in Risk For Intensive vs Conventional 34% 49% 32% 44%
Rigorous blood pressure control is paramount in minimizing adverse macrovascular outcomes Rigorous blood pressure control is at least as important in minimizing DRT as is rigorous blood glucose control
Why?
12
Diabetes Causes Defective Ocular Hemodynamics
Hyperglycemia impairs retinal vasoconstriction in response to increased blood flow and/or decreased intraocular pressure Proven by research using hyperoxic stimulus to vasoconstriction Microvasc Res. 2007 May;73(3):191-7 Invest Ophthalmol Vis Sci. 2009 Oct;50(10):4814-21
Autoregulation is defined as “the ability of a vascular bed to maintain constant blood flow to the tissues under conditions of varying perfusion pressure”. Variable blood pressure Variable IOP
How Does Hyperglycemia Increase Retinal Blood Flow?
Blood Flow (Q) Q
= ΔPлr4/8nl
small changes in radius (r) result in large increases in blood flow
ΔP = difference in arterial and venous pressure n = blood viscosity l = vessel length
Importance of BP Control
Hyperglycemia and Hypertension both contribute to increased Mean Arterial Pressure (MAP), Retinal Perfusion Pressure (RPP), and Blood Flow Diabetes causes defective retinal vascular auto-regulation leading to increased flow for any given RPP MAP and RPP may be highly predictive of Sight-Threatening DRT
Retinal Perfusion Pressure is the Equilibrium Between BP and IOP
Retinal blood flow is under local control; capillary endothelial pericytes regulate vasoconstriction in response to endothelin-1 (ET-1) Chronic hyperglycemia results in overexpression of ET-1 (reduced blood flow) but, ultimately, pericyte death leads to unchecked vasodilation Acta Ophthalmol Scand. 2002 Oct;80(5):468-77
Poiseuille’s Law
IOP BP Blood Pressure Increases Blood Flow Into the Eye
IOP Resists Blood Flow
Retinal blood flow is determined by the microvasculature’s ability to regulate RPP
13
Importance of BP Control
Vessel Stresses of Increased Blood Flow
Increased RPP & blood flow (volume/unit of time) into the eye causes:
Laminar Flow
– Shear Stress that damages capillary endothelium a retinal capillary closure and hypoxic stress – Shunting of blood flow to larger caliber vessels a decreased retinal capillary perfusion and hypoxic stress
v
FLOW
Circumferential Stress = RPP x Vessel Radius Wall Thickness Endothelial Shear Stress = RPP x Resistivity Index
Increased Blood Flow…
Reduced oxygenation of capillary bed
Hyperoxygenation of venous blood
Increased risk of severe NPDR and Proliferative DR
Graefes Arch Clin Exp Ophthalmol. 2009 Aug;247(8):1025-30 Invest Ophthalmol Vis Sci. 2013 Oct 29;54(10):7103-6
Retinal Perfusion Pressure
RPP is calculated from pressure in the CRA as measured by ophthalmodynamometry but may be closely approximated by measurement of blood pressure and IOP
RPP = 2/3(MAP) – IOP MAP = Mean Arterial Pressure MAP = (Systolic BP – Diastolic BP)/3 + Diastolic BP
Retinal Perfusion Pressure
Retinal perfusion pressure and pulse pressure: clinical parameters predicting progression to sight-threatening diabetic retinopathy British Journal of Diabetes & Vascular Disease Aug 2001;1(1):80-87 International Diabetes Federation, Paris 2003
14
Retinal Perfusion Pressure
Hemodynamic and biochemical data analyzed from a prospective database of Type 1 and Type 2 patients seen at the University of Warwick (UK) Diabetic Retinopathy Clinic from 19641994 (n= 1384) STR defined as development of CSME or PDR
Study Analysis
Results: Important Factors for STR
Type 1 Diabetes (n=457) – RPP p< 0.001 – Duration of Diabetes p=0.008 Type 2 Diabetes (n=927) – Mean Arterial Pressure p< 0.0001 – Diastolic Blood Pressure p< 0.001
Examples – case 1 BP = 120/80 and IOP = 20mm
4-6 x elevation in relative risk for STR when:
MAP = (120-80)/3 + 80 = 93.3mm RPP = 2/3 (93.3) - 20 = 42.2mm
What if IOP = 10mm
RPP
> 50.1 mm (Type 1) MAP > 97.1 mm (Type 2)
MAP = 93.3 mm RPP = 2/3 (93.3) – 10 = 52.2 mm Higher IOP lowers RPP
Examples – case 2 BP = 150/100 and IOP = 20mm MAP = (150-100)/3 + 100 = 116.6 mm RPP = 2/3 (116.6) - 20 = 57.8 mm
Uniqueness of Ocular Hemodynamics
Case 1 vs Case 2: a 25% rise in BP results in a 30-37% rise in RPP RPP rises faster (non-linearly) than BP
What if IOP = 10mm
MAP = 116.6 mm RPP = 2/3 (116.6) – 10 = 67.8 mm Higher IOP lowers RPP, but less so than does lowering blood pressure
Combined with defective vascular auto-regulation, this makes eyes of people with DM more susceptible to hypertensive insult
15
Relationship Between BP and RPP IOP = 30
100
Hemodynamics of STR
IOP = 20 IOP = 10
80
% Increase In RPP
60
– – – –
40 20
-40
-20
20
40
60
Hyperglycemia Systemic hypertension Pregnancy Ocular hypotension
80
-20 -40
Conditions that increase retinal blood flow increase the risk of severe DRT
% Increase In Blood Pressure
Concordant with UKPDS and WESDR findings but more predictive of STR
-60
Hemodynamics – “take home”
Diabetic eyes can’t tolerate elevated BP This is particularly true when blood glucose levels are chronically and significantly elevated
Beware unnecessarily treating OHTN in diabetes patients with poor glycemic control, inadequate hypertensive control and/or longstanding disease
Always measure/evaluate BP in patients with DM Consider Calculating MAP and RPP to gauge risk
Strategies For Prevention
Strategies For Preventing Diabetic Eye Disease
Tight glycemic control & limited glycemic variability to reduce production of ROS Pathway inhibitors if/when proven safe & effective -
Lutein & zeaxanthin Benfotiamine Pycnogenol Curcuminoids Vit D Lipoic Acid
16
Strategies For Prevention
Tight control of any HTN & dyslipidemia – ACEIs or ARBs – Fenofibrate in T2DM with NPDR
Calculate and improve RPP and MAP Patient/Doctor education and communication Prevention of diabetes!
The DPP Prevention
of Diabetes
– The Diabetes Prevention Program (DPP) conducted at 13 US centers showed that “lifestyle modification” lowered the risk of type 2 diabetes in those with pre-diabetes by 58%
Walk 30 minutes per day, five times per week
My Challenge to YOU!!
Don’t Simply Tell Patients They Need “Better Diabetes Control” Treat each patient as you would yourself or your family! – Individualize Your Care Based on Risk Factors and Emerging Science
DIVERSIFY
YOUR PORTFOLIO!
Prevention of Diabetes The Key Strategy The Diabetes Epidemic
Diabetic Eye Disease Kidney Disease Nerve Disease CV Disease
Understanding the Biochemistry and Hemodynamics of diabetic eye disease helps us to: Critically appraise scientific “breakthroughs” Formulate hypotheses and participate in scientific advancement Gauge risk for individual patients with diabetes Deliver better clinical information and care
Thank You!
Questions?
[email protected]
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