Emerging Trends in Diabetes and Diabetic Retinopathy

Anthony Cavallerano, OD, FAAOVA Boston Health Care System

New England College of OptometryBoston, Massachusetts

Anthony.cavallerano@va.gov

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