Transcript Diabetes “Detection” and “Care and Study” Demonstration

Emerging Trends in Diabetes and Diabetic Retinopathy
University of Milan
June 2007
Anthony Cavallerano, OD, FAAO
VA Boston Health Care System
New England College of Optometry
Boston, Massachusetts
[email protected]
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.
Diabetes: 20.8 Million and Climbing
• 14 million diagnosed + 6.8 million undiagnosed
• Type 2 diabetes accounts for 90-95% of cases
+60%
(Millions)
Diagnosed Cases
12
+17%
8
4
0
1980
1990
Centers for Disease Control and Prevention. 2006.
2000
May 16, 2006
Case Study CL
Case Studies - Patient CL
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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
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VA = 20/20 OD, 20/30 OS
Sensorimotor examination intact
SLE – early cataract OD
No evidence of NVI
Retinal 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 Retinopathy
Features
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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
CL - Notes
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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
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Clinical pearls
– Few HMa’s is not always reassuring
– Superior temporal quadrant
Diabetes Care Team
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PCP/ Internist/ Endocrinologist
Optometrist/ophthalmologist/retinologist
Nephrologist
Neurologist
Podiatrist
Mental health professional
Exercise Physiologist
Dietician/nutritionist
Diabetes educator
PATIENT
Current Therapies for
Microvascular Complications
Intervention
Glucose Control
Demonstrated Efficacy to Delay/Prevent
Retinopathy Nephropathy Neuropathy
LDL Control
+
+
?+
?
Aspirin
No
BP Control
ACE Inhibitors
Smoking Cessation
?
+
+
+
?
+
?
?
?
DCCT Evaluating
Type 1 Diabetes:
Intensive Blood Glucose Control
vs.
Standard Blood Glucose Control
Intervention Studies: Glycemic Control
DCCT*
(Type 1 diabetes)
10
9.1
Mean
8
HbA 1c
P< 0.001
7.2
Conventional therapy
Intensive therapy
(%)
6
0
N = 1,441 patients
*After 6.5 years
Adapted from DCCT Research Group. N Engl J Med. 1993;329:977-986.
14
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
Nephropathy†
Neuropathy
*Compared with conventional treatment
†Urinary albumin excretion  300 mg/24 h
Adapted from DCCT Research Group. N Engl J Med.
1993;329:977-986.
63%
54%
60%
15
UKPDS Evaluating
Type 2 Diabetes:
Intensive Blood Glucose Control
vs.
Standard Blood Glucose Control
similar results to DCCT
UKPDS: Study Overview
• 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: Intensive Glucose
Control in Type 2 Diabetes Mellitus
• 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
Risk reduction*
Microvascular disease
Retinopathy progression†
Microalbuminuria†
Myocardial infarction
*Compared with conventional therapy
†At 12 years
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
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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 highrisk 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 Syndrome
Diagnosis is established when 3 of these risk factors are present.
Risk Factor
Defining Level
Abdominal obesity
(Waist circumference)
Men
Women
TG
HDL-C
>102 cm (>40 in)
>88 cm (>35 in)
150 mg/dL
Men
Women
Blood pressure
Fasting glucose
<40 mg/dL
<50 mg/dL
130/85 mm Hg
110 mg/dL
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-2497.
Prevalence of the Metabolic
Syndrome Among US Adults
45
Men
Women
Prevalence (%)
40
35
30
25
20
15
10
5
0
20-29
30-39
40-49
50-59
Age (y)
Ford et al. JAMA. 2002;287:356.
60-69
70
Pathogenesis of Type 2 Diabetes
Insulin Resistance
Impaired b-Cell Function
Insulin Resistance and
Hyperinsulinemia With
Normal Glucose Tolerance
Insulin Resistance and
Declining Insulin Levels
With Impaired Glucose
Tolerance
Type 2 Diabetes
Adapted from Saltiel A, Olefsky JM. Diabetes. 1996;45:1661-1669.
Criteria for Diagnosis
FPG
Plasma glucose
(mg/dL)
2-h PPG (OGTT)
240
Diabetes
Mellitus
220
200
180
Diabetes
Mellitus
160
140
126
110
120
IFG
100
80
IGT
Normal
Normal
60
American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S5-S20
Risk Factors for Prediabetes
• Age
– 45 years or older
– Younger than 45, overweight, and have one or
more of the following risk factors:
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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
Vasculature
Increases:
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Basement matrix protein synthesis
Activation of leukocytes
Endothelial cell activation and proliferation
Smooth muscle cell contraction
Cytokine activation, TGF-b, 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
Event
Rate
Development of Moderate Vision Loss
50%
40%
Placebo
32 mg
30%
20%
10%
P = 0.019
0%
0
1
Years
2
3
Sustained* Losses in Visual Acuity
35
% of Patients
30
Placebo
(N=401 pt)
P=0.002
29.4%
RBX 32 mg/d
(N=412 pt)
25
20.9%
20
P=0.020
15.7%
15
P=0.011
10.9%
10.2%
10
6.1%
5
0
≥5
≥15 (SMVL)
≥10
ETDRS Letters Lost
Data from integrated analysis
*Sustained for
months 30-36,
or for the last
6 months on
study, for
patients who
discontinued
early
Diabetes: A Systemic Disease
Leading cause
of blindness
in working age
adults Diabetic
Retinopathy
Stroke
Diabetic
Nephropathy
2- to 4- fold
increase in
cardiovascular
mortality
and stroke
Cardiovascular
Disease
Leading cause of
end-stage renal disease
Diabetic
Neuropathy
Leading cause of non-traumatic
lower extremity amputations
National Diabetes Information Clearinghouse. Diabetes Statistics–Complications of Diabetes. (website)
http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp.
Vision Loss From Diabetes
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Diabetic macular edema
Vitreous hemorrhage
Tractional retinal detachment
Neovascular glaucoma
Diabetic Retinopathy
Prevalence
Type 1 DM (onset < 30 yrs)
13% < 5-yr-duration
UKPDS:
90% 10-15-yr-duration
~ 40% with DR
at entrance into study
Type 2 DM (onset > 30 yrs)
40% taking insulin
< 5-yr-duration
24% not taking insulin
< 5-yr-duration
84% taking insulin
15-20-yr-duration
53% not taking insulin
15-20-yr- duration
Wisconsin Epidemilogic Study of Diabetic Retinopathy (WESDR)
DME after 15 years of DM
• Type 1
20%
• Type 2 (insulin)
25%
• Type 2 (no insulin)14%
WESDR 1984
Case Presentation - SC
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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
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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
Mild H/Ma in midperiphery and posterior pole
Hard exudate within 1 DD of center of macula
Treatment Plan
No eye treatment indicated
Control DM and medical cx
Return 3 - 4 months
Mild to Moderate NPDR
Macular Edema Not CSME
Case Presentation - SC
Patient returned in six months
• VA/Ref: -1.50 sphere OU;20/40-2 OD/OS
• No progression of cataract
• No evidence of NVI
Additional medical history
• HbA1c = 6.4%
• Self-reported physical hx: Neg
• + ACE Inhibitor
• + bulimia nervosa
Case Presentation - SC
Treatment
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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
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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
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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
PDR at 1-year Visit By Severity of Retinopathy
70
60
50
40
Percent
30
20
10
0
(50)
(27)
(12)
(5)
Mild
Mod
Mod
Baseline Level
Sev
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 - AL
Initially does not appear to be severe
NPDR
Ischemia noted particularly in
midperiphery
Retinal embolus indicating significant risk
for cardiovascular disease
Increased association of ocular and
systemic vascular anomalies in patients
with DM
Other 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
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Hypertension (UKPDS, EUCLID)
Hyperlipidemia (ETDRS)
Abdominal Obesity (Eurodiab)
Anemia (ETDRS)
Future 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