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Emerging Trends in Diabetes and Diabetic Retinopathy
Anthony Cavallerano, OD, FAAOVA Boston Health Care System
New England College of OptometryBoston, Massachusetts
University of Milan
June 2007
Scope of the Problem
• Total: 20.8 million children and adults -- 7.0% of the population -- have diabetes.
• 10.3 million over age 60• Diagnosed: 14.6 million people• Undiagnosed: 6.2 million people• Pre-diabetes: 41 million people• 1.5 million new cases of diabetes were
diagnosed in people aged 20 years or older in 2005.
0
4
8
12
1980 1990 2000 Centers for Disease Control and Prevention. 2006.
Dia
gn
ose
d C
ases
(M
illio
ns)
+17%
+60%
• 14 million diagnosed + 6.8 million undiagnosed • Type 2 diabetes accounts for 90-95% of cases
Diabetes: 20.8 Million and Diabetes: 20.8 Million and ClimbingClimbing
May 16, 2006
Case Study CLCase Study CL
Case Studies - Patient CL
• 47-year-old female
• Type 1 DM x 26 years
• LEE - 6 months ago (undilated)
• Dilated retinal examination 2 years ago
• POHx – “mild retinopathy”
• No ocular or visual complaints
Case Studies - Patient CL
• VA = 20/20 OD, 20/30 OS
• Sensorimotor examination intact
• SLE – early cataract OD
• No evidence of NVI
Retinal Signs of HypoxiaRetinal Signs of Hypoxia• Cotton wool spots – 1/1 correlation with retinal
ischemia• Venous caliber abnormalities (VCAB)
– Change in course/dimension/direction of vessel– Venous beading
• Venous tortuosity• Intraretinal microvascular abnormalities
(IRMA) – 70% of NV occurs in areas of IRMA• Featureless retina
Diabetic RetinopathyDiabetic Retinopathy
Reduced retinal blood flow Closure of retinal capillaries and arterioles Ischemia/Cotton-wool spots Breakdown of the blood/retinal barrier with increased
vascular permeability of retinal capillaries Intraretinal microvascular abnormalities (IRMA) also found
adjacent to areas of capillary closure 70% of NVE occurs in same area as IRMA Proliferation of new vessels and fibrous tissue Contraction of vitreous and fibrous proliferation with VH
and RD
Features
CL - Notes• Little or no obvious NPDR on first glance• No ocular or visual complaints• Last exam 6 months ago/last dilated eye exam 2 years• High risk PDR and early DME• Three diagnoses
– NPDR– PDR– DME
• Clinical pearls– Few HMa’s is not always reassuring– Superior temporal quadrant
Diabetes Care TeamDiabetes Care Team
PCP/ Internist/ EndocrinologistPCP/ Internist/ Endocrinologist Optometrist/ophthalmologist/retinologistOptometrist/ophthalmologist/retinologist NephrologistNephrologist NeurologistNeurologist PodiatristPodiatrist Mental health professionalMental health professional Exercise PhysiologistExercise Physiologist Dietician/nutritionistDietician/nutritionist Diabetes educatorDiabetes educator
PATIENTPATIENT
Intervention Demonstrated Efficacy to Delay/Prevent
Retinopathy Nephropathy Neuropathy
Glucose Control + + +BP Control + +ACE Inhibitors ?+ +LDL Control ? ? ?Aspirin NoSmoking Cessation
? ? ?
Current Therapies for Microvascular Complications
DCCT Evaluating
Type 1 Diabetes:
Intensive Blood Glucose Control
vs.
Standard Blood Glucose Control
14*After 6.5 years
Intervention Studies: Glycemic Control
DCCT*(Type 1 diabetes)
Adapted from DCCT Research Group. N Engl J Med. 1993;329:977-986.
N = 1,441 patients
10
8
6
0
9.1
P < 0.001
7.2 Conventional therapy
Intensive therapy
Mean
HbA 1c
(%)
15
*Compared with conventional treatment†Urinary albumin excretion 300 mg/24 h
DCCT: Intensive Glucose Control in Type 1 diabetes mellitus
Compared to conventional insulin therapy, intensive insulin therapy reduced the risk of development and progression of:
Risk Reduction*
Retinopathy 63%
Nephropathy† 54%
Neuropathy 60%
Adapted from DCCT Research Group. N Engl J Med. 1993;329:977-986.
UKPDS Evaluating
Type 2 Diabetes:
Intensive Blood Glucose Control
vs.
Standard Blood Glucose Control
similar results to DCCT
• A 20-year, multicenter, prospective, randomized, interventional trial
• Recruited 5102 newly diagnosed type 2 diabetes patients – 40% with DR
• Mean duration from randomization: 11 years
• Randomized to intensive glucose control vs. conventional control
UKPDS: Study Overview
• Glycemic control deteriorated with time regardless of initial therapy
• Intensive glycemic control reduced HbA1c by 0.9% over 10 years, with resulting decrease in clinical complications
UKPDS: Intensive Glucose Control in Type 2 Diabetes Mellitus
*Compared with conventional therapy †At 12 years
Microvascular disease Retinopathy progression†
Microalbuminuria†
Myocardial infarction
Risk reduction*
25%21%
33%
16%
Role of Hypertension in DR
• Impairs retinal vascular autoregulation
• Promotes endothelial damage in retinal vasculature
• Increases expression of Vascular Endothelial Growth Factors (VEGF) and its receptors by vascular stretch of retinal endothelium
Role of Renal Disease in DME
• Gross proteinuria associated with 95% increased risk of DME (WESDR)
• Case reports of reduction of diabetic macular edema after dialysis
• Type 1 DM patients with microalbuminuria have three-fold risk of PDR compared to those with normal levels
Diabetic Nephropathy
• DM accounts for 30 – 40% of ESRD in the US• More common in Type 2 DM• Rarely develops in Type 1 DM before 10 years• 3% of Type 2 patients have nephropathy at the time
of diagnosis– Incidence is 3%/year– Peak incidence is DM of 10 – 20 years duration
Role of Serum Lipids in DR
• Elevated serum lipids are associated with increased risk of retinal hard exudates
• Increased amounts of hard exudates are associated with increased risk of visual impairment
• Elevated lipids, most notably triglycerides, are a risk factor for development of high-risk PDR
ETDRS Report # 18 and 22
Metabolic Syndrome
• Defined by the National Cholesterol Education Program. The presence of any three of the following conditions:
• Excess weight around the waist (waist measurement of more than 40 inches for men and more than 35 inches for women)
• High levels of triglycerides (150 mg/dL or higher)• Low levels of HDL cholesterol (below 40 mg/dL for
men and below 50 mg/dL for women)• High blood pressure (130/85 mm Hg or higher)• High fasting blood glucose levels (110 mg/dL or
higher)
The Metabolic SyndromeThe Metabolic SyndromeDiagnosis is established when 3 of these risk factors are present.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Risk Factor Defining LevelAbdominal obesity(Waist circumference)
Men Women
>102 cm (>40 in)>88 cm (>35 in)
TG 150 mg/dL
HDL-C
Men Women
<40 mg/dL<50 mg/dL
Blood pressure 130/85 mm Hg
Fasting glucose 110 mg/dL
Prevalence of the Metabolic Syndrome Among US Adults
0
5
10
15
20
25
30
35
40
45
20-29 30-39 40-49 50-59 60-69 70
Age (y)
Men
Women
Pre
vale
nc
e (
%)
Ford et al. JAMA. 2002;287:356.
Pathogenesis of Type 2 Diabetes
Insulin Resistance
Insulin Resistance and Hyperinsulinemia With
Normal Glucose Tolerance
Insulin Resistance and Declining Insulin Levels With Impaired Glucose
Tolerance
Type 2 Diabetes
Impaired -Cell Function
Adapted from Saltiel A, Olefsky JM. Diabetes. 1996;45:1661-1669.
Criteria for Diagnosis
American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S5-S20
FPG 2-h PPG (OGTT)
126 110
60
80
100
120
140
160
180
200
Plasma glucose(mg/dL)
Normal
Diabetes Mellitus
240
220
Diabetes Mellitus
Normal
IGT
IFG
Risk Factors for Prediabetes
• Age– 45 years or older– Younger than 45, overweight, and have one or more
of the following risk factors:• Family history of diabetes • Low HDL cholesterol and high triglycerides• Hypertension • History of gestational diabetes or gave birth to a baby
weighing more than 9 pounds• Minority group background
– African American– American Indian, Hispanic American/Latino– Asian American/Pacific Islander)
EXUBERA• Pfizer’s first FDA approved insulin inhaler
• Complementary to oral hypoglycemic agents
• Rapid-acting dry powder human insulin
• Inhaled into the mouth in powder form prior to eating
Januvia (sitagliptin phosphate)• Merck’s new entry into oral medications• Once per day dosage• Januvia prolongs the activity of proteins that
boost the release of insulin after blood sugar rises
• Januvia blocks the enzyme DPP-IV, (dipeptidyl peptidase-4) which breaks down these proteins.
• By sidelining that enzyme, Januvia lets those insulin-boosting proteins last longer, leading to better blood sugar control
• Side effects: URI, sore throat, diarrhea
Acomplia (rimonabant)• Sanofi-Aventis' obesity drug• 278 patients
– type 2 diabetes – not currently taking oral hypoglycemic agents
• QD dosage • Study results
– Those with A1c of 7.9% - lower by 0.8%– Those with A1c of >8.5% - lower by 1.9%– Average weight loss – 15lbs
• Reduced abdominal dimension by more than 6cm• Side effects Stock went up
– Dizziness, nausea, anxiety, depressed mood and headache (9% of study participants)
Pioglitazone/Rosiglitazone• Enhance insulin-mediated glucose disposal by
muscle, thereby decreasing insulin resistance• Rosiglitazone decreased risk of type 2 DM by
62% (DREAM Trial 2006)
• Associated with development of DME (risk—1/10,000)
• Rapid reduction of macular edema and peripheral edema with drug cessation
• Enhances the action of platinum-based cancer drugs and may reduce the risk for lung cancer
• May increase the risk for cardiac events
Ryan EH et al. Retina 2006; Kendall C et al. CMAJ 2006
Role of Protein Kinase C Activation in the Retinal
VasculatureIncreases:
– Basement matrix protein synthesis – Activation of leukocytes – Endothelial cell activation and proliferation– Smooth muscle cell contraction– Cytokine activation, TGF-, VEGF, endothelin– Angiogenesis– Endothelial permeability
The effect of ruboxistaurin (Arxxant) on visual loss in patients with moderately severe to very severe nonproliferative
diabetic retinopathy: Results of the Protein Kinase C beta Inhibitor Diabetic
Retinopathy Study (PKC-DRS) multicenter randomized clinical trial.
Diabetes. 2005 Jul;54(7):2188-97 .
PKC Beta Inhibitor Trials – Ruboxistaurin
20%
40%
0%
50%
EventRate
10 2 3
30%
10%
Placebo32 mg
Years
P = 0.019
Development of Moderate Vision Loss
Sustained* Losses in Visual Acuity
29.4%
20.9%
15.7%
10.9% 10.2%
6.1%
P=0.002
P=0.020
P=0.011
ETDRS Letters Lost
% o
f P
atie
nts
0
5
10
15
20
25
30
35
≥5 ≥15 (SMVL)≥10
Placebo (N=401 pt)
RBX 32 mg/d
(N=412 pt)
*Sustained for months 30-36, or for the last 6 months on study, for patients who discontinued early
Data from integrated analysis
Diabetes: A Systemic Disease
DiabeticRetinopathy
Leading causeof blindness
in working ageadults
DiabeticNephropathy
Leading cause of end-stage renal disease
CardiovascularDisease
DiabeticNeuropathy
Stroke
Leading cause of non-traumatic lower extremity amputations
2- to 4- fold increase in cardiovascular mortality and stroke
National Diabetes Information Clearinghouse. Diabetes StatisticsNational Diabetes Information Clearinghouse. Diabetes Statistics––Complications of Diabetes. (website) Complications of Diabetes. (website) http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp.http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp.
Vision Loss From Diabetes
• Diabetic macular edema
• Vitreous hemorrhage
• Tractional retinal detachment
• Neovascular glaucoma
Diabetic Retinopathy Prevalence
Wisconsin Epidemilogic Study of Diabetic Retinopathy (WESDR)
Type 1 DM (onset < 30 yrs)
13% < 5-yr-duration90% 10-15-yr-duration
Type 2 DM (onset > 30 yrs)
40% taking insulin < 5-yr-duration24% not taking insulin < 5-yr-duration84% taking insulin 15-20-yr-duration 53% not taking insulin 15-20-yr- duration
UKPDS:
~ 40% with DR
at entrance into study
DME after 15 years of DM
• Type 1 20%
• Type 2 (insulin) 25%
• Type 2 (no insulin) 14%
WESDR 1984
Case Presentation - SC
• 20-year-old female
• College freshman
• Type 1 DM 5.5 yrs
• Insulin: t.i.d., antidepressants, ACE-inhibitor
• c/o fluctuating vision
• SMBG 3-4 x day; Average ~ 300 mg/dL
Case Presentation - SC
• Recent HbA1c = 15.6%
(20 x 15.6) + 30 = 342
• Borderline HT; microalbuminuria
• Total cholesterol 202 mg/dL
Case Presentation - SC Exam Findings
• VA/Ref:– Cc (14 mos.): -1.50 sphere OU; 20/40-2 OD/OS– Refraction: -2.25 sphere OU; 20/20-2 OD/OS
• Sensorimotor exam normal
• Amsler grid: no distortion OD/OS
• IOP: 20 mm Hg OD/OS
• Cortical cataract OU, early PSC OD
• No evidence of NVI OD/OS
Hard exudate within 1 DD of center of maculaMild H/Ma in midperiphery and posterior pole
Mild to Moderate NPDR
Macular Edema Not CSME
Treatment Plan
No eye treatment indicated
Control DM and medical cx
Return 3 - 4 months
Case Presentation - SCPatient returned in six months• VA/Ref: -1.50 sphere OU;20/40-2 OD/OS• No progression of cataract• No evidence of NVIAdditional medical history • HbA1c = 6.4%• Self-reported physical hx: Neg• + ACE Inhibitor• + bulimia nervosa
Case Presentation - SC
Treatment • Focal and scatter laser treatment stat OD• Focal Laser OS • PRP x 3 OD over 2.5 mo• PRP x 4 OS over 2.5 mo
• Report/discussion with patient and endocrinologist
Case Study AL
Case Studies - Patient AL
• 36-year-old male • Type 1 DM 25 yrs• LEE 2–3 yrs• PMHx: mitral valve stenosis,valve
replacement• FOHx: glaucoma (grandmother)• Recent HbA1c = 7.0%• Insulin, Lasix, coumadin, vitamins A,C,D,
zinc, calcium
Case Study AL
• VA 20/20 OU
• Sensorimotor exam normal
• Amsler grid: no distortion OU
• IOP 17mmHg OU
Case Study AL
Treatment Plan
• Follow-up in 3 months
• Referral for cardiovascular/carotid evaluation
• Hypertension control
ETDRS
(5)(12)
(27)
(50)
0102030
40506070
Percent
Mild Mod Mod Sev
Baseline Level
PDR at 1-year Visit By Severity of Retinopathy
Retinal Emboli Cholesterol - sparkling yellow/ glistening –
typically at an arterial bifurcation (carotid artery disease)
Calcium – dull, fluffy, chalky white – around disc (cardiac disease)
Cardiac myxoma - seen in young patients, typically in the left eye – often occludes ophthalmic or central retinal arteries
Talc or cornstarch – i.v. drug abuse
Notes - ALInitially does not appear to be severe NPDRIschemia noted particularly in midperipheryRetinal embolus indicating significant risk for
cardiovascular diseaseIncreased association of ocular and systemic
vascular anomalies in patients with DMOther vascular disorders influence the
development and rate of progression of DR
Yesterday/Today: Therapy for Diabetic Retinopathy
• Laser Surgery/Pars Plana Vitrectomy (ETDRS)
• Intensive glycemic control (DCCT/EDIC, UKPDS)
• Control of concurrent systemic disorders– Hypertension (UKPDS, EUCLID)
– Hyperlipidemia (ETDRS)
– Abdominal Obesity (Eurodiab)
– Anemia (ETDRS)
Future ImplicationsFuture Implications
• Eventual move beyond an era of common pathway late-stage complication-oriented therapy
• Move toward earlier therapies targeted to specific molecules mediating disease-specific and/or risk- factor-specific interactions
• Therapies targeted to specific individuals