Emerging Trends in Diabetes and Diabetic Retinopathy

1
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
• Anthony.cavallerano_at_va.gov

2
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.

3
Diabetes 20.8 Million and Climbing

• 14 million diagnosed 6.8 million undiagnosed
• Type 2 diabetes accounts for 90-95 of cases

60
12
17
8
Diagnosed Cases (Millions)
4
0
1980
1990
2000
Centers for Disease Control and Prevention. 2006.
4
                      May 16, 2006    
5
Case Study CL
6
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

7
Case Studies - Patient CL

• VA 20/20 OD, 20/30 OS
• Sensorimotor examination intact
• SLE early cataract OD
• No evidence of NVI

8
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

9
Diabetic Retinopathy
Features

• 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

10
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 HMas is not always reassuring
• Superior temporal quadrant

11
Diabetes Care Team

• PCP/ Internist/ Endocrinologist
• Optometrist/ophthalmologist/retinologist
• Nephrologist
• Neurologist
• Podiatrist
• Mental health professional
• Exercise Physiologist
• Dietician/nutritionist
• Diabetes educator

PATIENT
12
Current Therapies for Microvascular Complications
Intervention Demonstrated Efficacy to Delay/Prevent Retinopathy Nephropathy Neuropathy Demonstrated Efficacy to Delay/Prevent Retinopathy Nephropathy Neuropathy Demonstrated Efficacy to Delay/Prevent Retinopathy Nephropathy Neuropathy
Glucose Control
BP Control
ACE Inhibitors ?
LDL Control ? ? ?
Aspirin No
Smoking Cessation ? ? ?
13
DCCT Evaluating

• Type 1 Diabetes
• Intensive Blood Glucose Control
• vs.
• Standard Blood Glucose Control

14
Intervention Studies Glycemic Control
DCCT(Type 1 diabetes)
10
9.1
Mean
P
lt 0.001
8
Conventional therapy
HbA
7.2
1c
Intensive therapy
()
6
0
N 1,441 patients
After 6.5 years
Adapted from DCCT Research Group. N Engl J Med.
1993329977-986.
15
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
Compared with conventional treatment Urinary
albumin excretion ? 300 mg/24 h
Adapted from DCCT Research Group. N Engl J Med.
1993329977-986.
16
UKPDS Evaluating

• Type 2 Diabetes
• Intensive Blood Glucose Control
• vs.
• Standard Blood Glucose Control
• similar results to DCCT

17
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

18
UKPDS

• 37 39 had retinopathy at baseline
• WESDR showed 21 - mean A1c was 10.37)
• Intensive control showed
• 34 reduction in progression of retinopathy
• 29 reduction in need for laser treatment
• 16 reduction in legal blindness

19
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
25
21
33
16
Compared with conventional therapy At 12 years
20
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

21
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

22
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

23
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
24
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)

25
The Metabolic Syndrome
Diagnosis is established when ?3 of these risk
factors are present.
Risk Factor Defining Level
Abdominal obesity(Waist circumference) Men Women gt102 cm (gt40 in)gt88 cm (gt35 in)
TG ?150 mg/dL
HDL-C Men Women lt40 mg/dLlt50 mg/dL
Blood pressure ?130/?85 mm Hg
Fasting glucose ?110 mg/dL
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-2497.
26
Prevalence of the Metabolic Syndrome Among US
Adults
45
Men
40
Women
35
30
25
Prevalence ()
20
15
10
5
0
20-29
30-39
40-49
50-59
60-69
?70
Age (y)
Ford et al. JAMA. 2002287356.
27
Pathogenesis of Type 2 Diabetes
Insulin Resistance
Impaired b-Cell Function
Insulin Resistance and Hyperinsulinemia
WithNormal Glucose Tolerance
Insulin Resistance and Declining Insulin Levels
With Impaired Glucose Tolerance
Type 2 Diabetes
Adapted from Saltiel A, Olefsky JM. Diabetes.
1996451661-1669.
28
Criteria for Diagnosis
FPG
2-h PPG (OGTT)
Plasma glucose (mg/dL)
240
Diabetes Mellitus
220
200
Diabetes Mellitus
180
IGT
160
140
126
120
IFG
110
Normal
100
Normal
80
60
American Diabetes Association. Diabetes Care.
200326(suppl 1)S5-S20
29
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)

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EXUBERA

• Pfizers 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

31
Januvia (sitagliptin phosphate)

• Mercks 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

32
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 gt8.5 - 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)

33
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
  (risk1/10,000)
• 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
34
Role of Protein Kinase C Activation in the
Retinal Vasculature

• Increases
• Basement matrix protein synthesis
• Activation of leukocytes
• Endothelial cell activation and proliferation
• Smooth muscle cell contraction
• Cytokine activation, TGF-?, VEGF, endothelin
• Angiogenesis
• Endothelial permeability

35
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
Jul54(7)2188-97 .
36
PKC Beta Inhibitor Trials Ruboxistaurin
Event Rate
Development of Moderate Vision Loss
50
Placebo
40
32 mg
30
20
10
P 0.019
0
1
0
2
3
Years
37
Sustained Losses in Visual Acuity
Sustained for months 30-36, or for the last 6
months on study, for patients who discontinued
early
Data from integrated analysis
38
Diabetes and Dementia

• 4.5 million Americans (1 in 10 over age 65, half
  over 85) with demented disorders - 12 16
  million by 2050
• Risk of developing dementia is twice as great in
  diabetes
• Type 3 diabetes form of the disese affecting
  the nervous system
• Insulin resistance - hyperinsulinemia
• Inflammation
• Leads to amyloid buildup in the brain
• Risk of dementia is in borderline diabetics with
  hypertension

39
Diabetes and Dementia
Risk for dementia based on HbA1c
gt7.0 No or low risk
10.0 11.9 13 increased risk
12.0 14.9 24 increased risk
Study showed life-long benefit of intensive
glycemic control
Whitmer et al
40
Diabetes A Systemic Disease
National Diabetes Information Clearinghouse.
Diabetes StatisticsComplications of Diabetes.
(website) http//www.niddk.nih.gov/health/diabetes
/pubs/dmstats/dmstats.htmcomp.
41
Vision Loss From Diabetes

• Diabetic macular edema
• Vitreous hemorrhage
• Tractional retinal detachment
• Neovascular glaucoma

42
Diabetic Retinopathy Prevalence

• Type 2 DM (onset gt 30 yrs)
• 40 taking insulin
• lt 5-yr-duration
• 24 not taking insulin
• lt 5-yr-duration
• 84 taking insulin
• 15-20-yr-duration
• 53 not taking insulin
• 15-20-yr- duration

• Type 1 DM (onset lt 30 yrs)
• 13 lt 5-yr-duration
• 90 10-15-yr-duration

UKPDS 40 with DR at entrance into study
Wisconsin Epidemilogic Study of Diabetic
Retinopathy (WESDR)
43
DME after 15 years of DM

• Type 1 20
• Type 2 (insulin) 25
•  
• Type 2 (no insulin) 14

WESDR 1984
44
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

45
Case Presentation - SC

• Recent HbA1c 15.6
• (20 x 15.6) 30 342
• Borderline HT microalbuminuria
• Total cholesterol 202 mg/dL

46
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

47

• Treatment Plan
• No eye treatment indicated
• Control DM and medical cx
• Return 3 - 4 months

48
Case Presentation - SC

• Patient returned in six months
• VA/Ref -1.50 sphere OU20/40-2 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

49
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

50
Case Study AL
51
Case Studies - Patient AL

• 36-year-old male
• Type 1 DM 25 yrs
• LEE 23 yrs
• PMHx mitral valve stenosis,valve replacement
• FOHx glaucoma (grandmother)
• Recent HbA1c 7.0
• Insulin, Lasix, coumadin, vitamins A,C,D, zinc,
  calcium

52
Case Study AL

• VA 20/20 OU
• Sensorimotor exam normal
• Amsler grid no distortion OU
• IOP 17mmHg OU

53
Case Study AL

• Treatment Plan
• Follow-up in 3 months
• Referral for cardiovascular/carotid evaluation
• Hypertension control

54
ETDRS
55
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

56
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

57
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)

58
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