1

Diabetes

and

Cardiovascular Disease

Satellite Conference and Live WebcastWednesday, March 5, 2008

2:00-4:00 p.m. (Central Time)

Produced by the Alabama Department of Public HealthVideo Communications and Distance Learning Division

Beverly Stoudemire-Howlett, M.D.Cardiologist

Montgomery CardiovascularAssociates &

Montgomery Links Incorporated

Faculty

Diabetes• 21 million Americans have diabetes and

284,000 die from it each year.

• 65% of the deaths are related tocardiovascular causes.

• Type 2 diabetes increases the risk forheart disease 2 to 4 times.

• The Diabetes Education Grouprecommends a HgAlC 7% for Type 2Diabetes.

What is Diabetes?

• Diabetes is a group of diseasescharacterized by high levels of bloodglucose (blood sugar).

• Diabetes can lead to serious healthproblems and premature death.

Diabetes Complications• 2 in 3 people with diabetes die of heart

disease or stroke.

• Diabetes is the #1 cause of adultblindness.

• Diabetes is the #1 cause of kidneyfailure.

• Diabetes causes more than 60% of non-traumatic lower-limb amputations eachyear.

Common Types of Diabetes

Type 1 diabetes

• 5% to 10% of diagnosed cases ofdiabetes.

Type 2 diabetes

• 90% to 95% diagnosed cases ofdiabetes.

2

Obesity Trends1990 2001

20011990 Diabetes Trends

U.S. Diabetes PrevalenceAll Ages, 2005

20.8 million people have diabetes.

• Diagnosed: 14.6 million people

• Type 1 diabetes accounts for 5 –10%

• Type 2 diabetes accounts for 90 –95%

• Undiagnosed: 6.2 million people

U.S. Diabetes Prevalence20 Years or Older, 2005

25

20

15

10

5

0

Percent

Age Group20-39 40-59 60+

U.S. Diabetes Prevalence20 Years or Older, by Race/Ethnicity, 2005

0 4 8 1 2 1 6 2 0

American Indians and AlaskaNatives and Diabetes

• 12.8 percent of American Indians and

Alaska Natives had diabetes in 2003.

• 2.2 times as likely to have diabetes as

non-Hispanic whites.

African Americansand Diabetes

• 13.3 percent of all African Americans

have diabetes.

• African Americans are 1.8 times as

likely to have diabetes as non-Hispanic

whites.

3

Hispanic/Latino Americansand Diabetes

• 9.5 percent of all Hispanic/Latino

Americans have diabetes.

• Mexican Americans are 1.7 times as

likely to have diabetes as non-Hispanic

whites.

Preventing DiabetesComplications

• Glucose control

• Blood pressure control

• Blood lipid control

• Preventive care practices for eyes,

kidneys, feet, teeth and gums

• Aspirin as directed by physician

What is Pre-Diabetes?• People with pre-diabetes have blood

glucose levels higher than normal butnot high enough to be diagnosed withdiabetes.

• People with pre-diabetes can prevent ordelay the onset of type 2 diabetesthrough lifestyle change and/ormedication - though none are approvedfor diabetes prevention.

Pre-Diabetes

• At least 54 million U.S. adults age 20

and older have pre-diabetes—which

raises their risk for type 2 diabetes and

cardiovascular disease.

Other Factors for Pre-Diabetes• Hypertension• Abnormal lipid levels• Family history of

diabetes• Race/ethnicity• History of

gestational diabetes• History of vascular

disease• Signs of insulin

resistance

• PCOS

• Previous IGT orIFG

• Inactive lifestyle

Metabolic Syndrome

• Also termed Insulin Resistance - The

concurrence of multiple metabolic

abnormalities associated with

cardiovascular disease.

• 1/3 of US Adults have Metabolic

Syndrome.

4

Definition of MetabolicSyndrome

• Hyperglycemia (Glucose intolerance)

• Abdominal Obesity (Central Obesity)

• Hypertriglyceridemia (Dyslipidemia)

• Low High Density Lipoproteincholesterol

• Hypertension

• Increased Prothrombotic andAntifibrinolytics (Lp(a), Lp-PLA2)

Risk of CV Events

• 3 or more Coronary Risk Fators.

• Evaluation of several large longitudinal

studies suggest increased risk of CV

events and death in people with

MetSyn.

• CV risk conferred by MetSyn is a third

higher in women than men.

Alabama vs Nation Adult RiskFactor Data

30.5

10

31.2

38.3

25.1

7.5

25.5

35.6

05

1015202530354045

Obe

sity

Diabe

tes

Hyper

tens

ion

High

Cholest

erol

Perc

en

t

AlabamaNation

30.5

10

31.2

38.3

25.1

7.5

25.5

35.6

05

1015202530354045

Obe

sity

Diabe

tes

Hyper

tens

ion

High

Cholest

erol

Perc

en

t

AlabamaNation

Alabama vs Nation Adult RiskFactor Data

29.7

20.123.8 23.2

0

5

10

15

20

25

30

35

Physically Inactive Consume fruits orvegetables 5 or more

time daily

Pe

rce

nt

AlabamaColumn 2

29.7

20.123.8 23.2

0

5

10

15

20

25

30

35

Physically Inactive Consume fruits orvegetables 5 or more

time daily

Pe

rce

nt

AlabamaColumn 2

Treatment

• Target individualrisk factors

• Primary prevention

trials of aggressive

• Dietary

• Lifestyle

• Pharmocologic

interventions

Risk Factors for Diabetes• Older age

• Overweight (BMI ≥ 25)

• Hypertension

• Abnormal lipid levels

• Family history of diabetes

• Race/ethnicity

• History of gestational diabetes

5

Risk Factors for Diabetes

• History of vascular disease

• Signs of insulin resistance

• PCOS

• Previous IGT or IFG

• Inactive lifestyle

Diabetes Control andComplications Trial (DCCT)

• Compared effects of two diabetes

treatment regimens – standard

therapy and intensive control – on the

complications of diabetes.

• Glucose control is key to preventing or

delaying complications of diabetes.

• Any sustained lowering of blood

glucose helps, even if the person has a

history of poor control.

DCCT Findings DCCT Findings

Lowering blood glucose reduced risk of:

• Eye disease by 76%

• Kidney disease by 50%

• Nerve disease by 60%

United Kingdom ProspectiveDiabetes Study (UKPDS)

Clinical Trial

Looked at intensive management ofblood glucose levels and long termrisk-factors for diabetes complications.

• Mirrored the findings of DCCT in people with type 2 diabetes—better glucose control reduced development of microvascular complications.

• Demonstrated the need for management of high blood pressure and cholesterol as well as blood glucose levels (the ABCs of diabetes).

UKPDS Findings

6

UKPDS Findings

P <.0001 P = .035 P = .021P =

.0001

Risk reduction with 1% decline in annualmean A1C

Micro-vascularDisease

37%

PVD

43%

StrokeMI

14% 12%

HeartFailure

CataractExtraction

16% 19%

0%

15%

30%

45%

Epidemiology of DiabetesInterventions and

Complications Study (EDIC)

• Observational study

• DCCT participants

• Looked at risk factors for long-term

complications

• Participants continue to benefit frommetabolic memory of intense glucose control

• Intensive therapy aimed at achievingnear normoglycemia:

• Reduces CVD events by more than half

• Should be implemented as earlyas possible

EDIC Findings: IntensiveTherapy and Diabetes

Complications

EDIC Findings: Cardiovascular EventsC

um

ula

tive

Inci

den

ce

Years from Study Entry

Cumulative Incidence of First of Any Event

0 2 4 6 8 10 12 14 16 18 20

Risk reduction 42%95% CI: 9% to 63%P = 0.02

0.12

0.10

0.08

0.06

0.04

0.02

0.00

Conventional

Intensive

EDIC Findings: Cardiovascular Events

Conventional

Intensive

Non-Fatal MI, Stroke, or CVD Death

0 2 4 6 8 10 12 14 16 18 20Years from Study Entry

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Cu

mu

lati

ve In

cid

ence

Risk reduction 57%95% CI: 12% to 79%P = 0.02

• The DPP was a major clinical trial to

determine whether diet and

exercise or the oral diabetes drug

metformin could prevent or delay

the onset of type 2 diabetes.

Diabetes Prevention Program(DPP)

7

DPP ParticipantsAdults at high risk for type 2 diabetes• Presence of IGT• Mean age 51 years• Mean body mass index (BMI) 34• 68% women• 45% minority groups:

• African Americans• Hispanic and Latino Americans• American Indians• Asian Americans and Pacific

Islanders

DPP Methods• Lifestyle intervention

- 5% to 7% weight reduction- Healthy low-calorie, low-fat diet- 30 min. of physical activity,

5 days/week

• Metformin- Oral diabetes drug

• Placebo

DPP Methods• DPP Curriculum:

– Diet

– Exercise

– Behavior change modification

• Taught one-on-one by case managers

Incidence of Diabetes

0 1 2 3 4

0

10

20

30

40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent developing diabetes

All participants

All participants

Years from randomization

Cu

mu

lative

in

cid

en

ce

(%

)

0 1 2 3 4

0

10

20

30

40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent developing diabetes

All participants

All participants

Years from randomization

Cu

mu

lative

in

cid

en

ce

(%

)

Placebo (n=1082)

Metformin (n=1073, p<0.001 vs. Placebo)Lifestyle (n=1079, p<0.001 vs. Metformin, p<0.001 vs. Placebo)

Incidence of Diabetes

Risk reduction31% by metformin58% by lifestyle

Diabetes Prevention

• Type 2 diabetes prevention is:

– PROVEN

– POSSIBLE, and

– POWERFUL

Testing Recommendations forPeople at High Risk

• Consider testing plasma glucose if aperson is:

– Age 45 or older and overweight.

– Younger than 45, overweight, withany additional risk factor.

• Repeat testing at 3-year intervals.

• Obtain FPG or 2-hour plasma glucosepost 75-g glucose challenge after overnight 8 to 12 hr fast.

8

Diagnostic Criteria forPre-diabetes and Diabetes

Fasting PlasmaGlucose Test

(FPG)

2-Hour OralGlucose

Tolerance Test(OGTT)

Normal Below 100 mg/dl Below 140 mg/dl

Pre-diabetes

100-125 mg/dl (IFG) 140-199 mg/dl (IGT)

Diabetes 126 mg/dl or above 200 mg/dl or above

ACCORD• 10,251 Participants.

• 257 in the intensive treatment groupdied. HgbAlc less than 6.

• 203 in the standard treatment group.

• Trial end June 2009 now the intensiveand standard tx groups will be thesame.

ACCORD

• Intensively reducing blood sugar belowguidelines causes harm in high risktype 2 diabetes patients.

• Standard tx arm will continue.

• Seek answer for cause of death in theintense group.

The standard treatment arm

Effects of treatments for blood pressure

Effects of treatments for blood lipids

The results of ACCORD does not apply

to patients with type I Diabetes

Unclear if applies to recently

diagnosed type 2

Action to ControlCardiovascular Disease in

Diabetes

Diminished Benefit of LoweringLDL-C Substantially Below 100

mg/dL in High-Risk Patients

22% RiskReduction 32% Risk

Reduction

25.1

0

5

10

15

20

25

30

Placebo Simvastatin

13.4

ResidualCVD Risk Residual

CVD Risk

20.2

9.4

0

2

4

6

8

10

12

14

16

Placebo Atorvastatin

Acu

te C

VD

Eve

nt

Rat

e, %

Residual CVD Risk in DiabeticPatients Treated With Statins

CARDSN = 2838

HPS: Patients With Diabetesn = 5963

Maj

or

Vas

cula

r E

ven

t R

ate,

%

9

Diabetic Patients Have Particularly HighResidual CVD Risk After Statin Treatment

17.9%13.8%9.7%7.8%TNT6_

OnPlacebo

On StatinOn PlaceboOn Statin

11.4%9.6%8.7%4.9%ASCOT-LLA5‡

18.4%23.1% 16.0%13.1%PROSPER4§

22.8%19.2%15.2%11.7%LIPID3‡

36.8%28.7%24.6%19.4%CARE2†

37.8%25.7%19.8%HPS1* (CHDpatients) 33.4%

Event Rate(Diabetes)

Event Rate (NoDiabetes)

Residual CVD Risk in Patients TreatedWith Intensive Statin Therapy

Pat

ien

ts E

xper

ien

cin

g

Maj

or

CV

D

Eve

nts

, % Standard statin therapy

Intensive high-dose statin therapy

PROVE IT-TIMI 222 IDEAL3 TNT4

N

LDL-C,*mg/dL

4162 8888 10 001

95 62 104 81 101 77

Statistically significant, but clinically inadequate CVD reduction1

The Role of ElevatedTriglycerides and LowHDL-C in Residual CVD

Risk

VisceralAdiposopathy

FFA

Fatty LiverCholesterol

Ester

TG CETP

CETP

CholesterolEster

Lipases

Lipases

TG

Renal Clearance

Small, Dense LDL

Small,Dense HDL

TG

TG

TG

HDL

LDL

VLDL

Dyslipidemia and Particle Size:Role of CETP

0

1

2

3

100 160 220 8565

4525

0

1

2

3

100 160 220 8565

4525

HDL-C Is a Modifier of Riskat All Levels of LDL-C

The Framingham Study*

LDL-C, mg/dL HDL-C, mg/dL

Ris

k o

f C

HD

*Men 50 to 70 years of age

3

21

4Equivalent Risk

Patient 1LDL-C 100 mg/dLHDL-C 65 mg/dLRisk level 0.4

Patient 2LDL-C 100 mg/dLHDL-C 45 mg/dLRisk level 0.6

Patient 3LDL-C 100 mg/dLHDL-C 25 mg/dLRisk level 1.2

Patient 4LDL-C 220 mg/dLHDL-C 45 mg/dLRisk level 1.2

HDL

HDL and Reverse CholesterolTransport

Pre-β-HDL is

produced by

the liver

Benefits in Reducing Atherosclerosis

10

ADA/AHA 2007 Scientific Statement:Primary Prevention of CVD in Patients With

Diabetes• Elevated LDL-C is primary target of

lipid-lowering therapy

• LDL-C goal <100 mg/dL

• TG-rich lipoproteins, especially VLDL,are often elevated in patients withdiabetes, appear to be atherogenic, andrepresent a secondary target of lipid-lowering therapy.

ADA/AHA 2007 Scientific Statement:Primary Prevention of CVD in Patients With

Diabetes• TG goal <150 mg/dL; HDL-C goal >40

mg/dL*

• If TG are 200-499 mg/dL, non–HDL-Cgoal ≤130 mg/dL

• If TG are ≥500 mg/dL, lowering TG isprimary target

• Combination therapy of LDL-cholesterollowering drugs (statins) with fibrates orniacin may be necessary to achieve lipidtargets

ADA

AHA

HDL-C

Raising

Goal: >40

mg/dL†

LDL-C

Lowering

Goal:

<100mg/dL*

Second Priority

•Niacin‡ or fibrates•TLC

•Niacin, ezetimibe, bile

acid sequestrants, or

fenofibrate

•TLC

•Statins

First Priority

American Diabetes AssociationStandards of Medical Care in Diabetes:

Dyslipidemia Management

•Glycemic control + statin+ fibrate

•Glycemic control + statin+ niacin‡

•Glycemiccontrol +high-dosestatin

Combined

Hyperlipidma

•Fibrates (fenofibrate,gemfibrozil)

•Niacin‡

•Statins (if also have highLDL-C)

•TLC

•Glycemiccontrol

TG Lowering

Goal: <150mg/dL

Second PriorityFirst Priority

American Diabetes AssociationStandards of Medical Care in Diabetes:

Dyslipidemia Management

National Guidelines:Niacin Therapy

NCEP ATP III Guidelines1

• “Among lipid-lowering agents, nicotinicacid appears to be the most effectivefor favorably modifying all of thelipoprotein abnormalities associatedwith atherogenic dyslipidemia.”

ADA/AHA 2007 Scientific Statement2

• “The most effective available drug forraising HDL-cholesterol levels isnicotinic acid.”

Summary

• Diabetes is preventable.

• Cornary Artery Disease is preventable.

• Decrease the incidence ofcardiovascular events.

• Decrease the incidence of stroke.

• Decrease the incidence of severity ofcongestive heart failure.

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