Heart Disease in Women: New Concepts in Prevention and

Managementof Dyslipidemia and Other Risk Factors

Nathan D. Wong, PhD, FACC

Professor and Director

Heart Disease Prevention Program

Division of Cardiology

University of California, Irvine

Cardiovascular Disease in Women

• 38.2 million women (34%) are living with cardiovascular disease and a much larger population is at risk.

• Heart disease and stroke are the no. 1 and no. 3 killers of women over age 25

• 1 in 30 die of breast cancer, but 1 in 2.5 die of cardiovascular disease or stroke.

• 66,000 more women than men die per year of cardiovascular disease; represents 54% of deaths in women compared to 46% in men.

AHA Heart Disease and Stroke Statistics 2004 Update, and Mosca et al., Circulation 2007; 115: 1481-1501.

Cardiovascular disease mortality trends for males and Cardiovascular disease mortality trends for males and females females (United States: 1979-2004). United States: 1979-2004). Source: NCHS and NHLBI.Source: NCHS and NHLBI.

380

400

420

440

460

480

500

520

79 80 85 90 95 00 04

Years

Dea

ths

in T

ho

usa

nd

s

Males Females

0

Note: Hospital discharges include people discharged alive, dead, and status Note: Hospital discharges include people discharged alive, dead, and status unknown.unknown.

Hospital discharges for coronary heart disease by sexHospital discharges for coronary heart disease by sex (United States: 1970-2004). (United States: 1970-2004). Source: NHDS, /NCHS and NHLBI. Source: NHDS, /NCHS and NHLBI.

Note: Hospital discharges include people discharged alive, dead and status unknown..

Hospital discharges for heart failure by sex(United States: 1979-2004). Source: NHDS, NCHS and NHLBI.

10.1

21.4

34.6

59.2

4.28.9

40.2

74.4

20.0

65.2

010

2030

4050

6070

80

45-54 55-64 65-74 75-84 85-94

Age

Pe

r 1

,00

0 P

ers

on

Ye

ars

Men Women

Incidence of cardiovascular disease* by age and sex* Includes CHD, HF, stroke or IC. Source: FHS, 1980-2003. NHLBI.

410

285

70 5935

461

265

6447 38

0

100

200

300

400

500

A B C D E A B D F E

MalesFemales

Deaths in ThousandsDeaths in Thousands

A Total CVDB CancerC Accidents

D Chronic Lower Respiratory DiseasesE Diabetes MellitusF Alzheimer’s DiseaseLeading causes of death for all males and females

(United States: 2004). Source: NCHS and NHLBI.

Estimated 10-Year Stroke Risk in 55-Year-Old Adults According to Levels of Various Risk Factors – Framingham Heart Study

p16

AA B B C C D D E E F F

Systolic BPSystolic BP** 95-10595-105 130-148130-148 130-148130-148 130-148 130-148 130-148130-148 130-148 130-148

DiabetesDiabetes No No No No Yes Yes Yes Yes Yes Yes Yes Yes

CigarettesCigarettes No No No No No No Yes Yes Yes Yes Yes Yes

Prior Atrial FibrillationPrior Atrial Fibrillation No No No No No No No No Yes Yes Yes Yes

Prior CVDPrior CVD No No No No No No No No No No Yes Yes

* * Blood pressures are in millimeters of mercury (mm Hg).Blood pressures are in millimeters of mercury (mm Hg).

Source: Wolf, PA, et al. Stroke. 1991;22:312-318.

Say ALOHA to Heart Disease in Women

• A – Assess your risk: high, intermediate, or low?

• L – Lifestyle recommendations are first priority

• O – Other interventions prioritized according to expert panel rating scale

• H – Highest priority for therapy is for women at highest risk

• A – Avoid medical therapies called Class III where evidence is lacking

Mosca L. Circulation 2004

A - Assessment of CHD Risk Classification of CVD Risk in

Women (Mosca et al., Circ 2007)• High Risk:

– Established coronary heart disease– Cerebrovascular disease– Peripheral arterial disease– Abdominal aortic aneurysm– End-stage or chronic renal disease– Diabetes mellitus– 10-year Framingham global risk >20%

Classification of CVD Risk in Women (Mosca et al., Circ 2007)

• At Risk:– Evidence of subclinical vascular disease (e.g., coronary calcium)– Metabolic Syndrome– Poor exercise capacity on treadmill and/or abnormal heart rate

recovery– >=1 major risk factor for CVD including:

• Cigarette smoking• Poor diet• Physical inactivity• Obesity (esp central obesity)• Family history of premature CVD (<55 male or <65 female relative)• Hypertension• Dyslipidemia

• Optimal risk: Framingham global risk <10% and a healthy lifestyle with no risk factors

For persons without known CHD, other forms of atherosclerotic disease, or diabetes:

• Count the number of risk factors.• Use Framingham scoring if 2 risk factors* to determine the

absolute 10-year CHD risk.• Determine risk status: high (>20% 10-year risk or CHD risk

equivalents), intermediate (10-20% 10-year risk), or low (<10% risk)

*For persons with 0–1 risk factor, Framingham calculations are not necessary.

Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. © 2001, Professional Postgraduate Services®

www.lipidhealth.org

Point Total 10-Year Risk Point Total 10-Year Risk

<9 <1% 2011%

9 1% 2114%

10 1% 2217%

11 1% 2322%

12 1% 2427%

13 2% 25 30%

14 2%15 3%16 4%17 5%18 6%19 8%

Assessing CHD Risk in Women

Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Step 1: Age

YearsPoints

20-34 -735-39 -340-44 045-49 350-54 655-59 860-64 1065-69 1270-74 1475-79 16

TC Points at Points at Points at Points atPoints at(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69

Age 70-79 <160 0 0 0 0

0160-199 4 3 2 1

1200-239 8 6 4 2

1240-279 11 8 5 3

2280 13 10 7 4

2

HDL-C(mg/dL) Points

60 -1

50-59 0

40-49 1

<40 2

Step 3: HDL-Cholesterol

Systolic BP PointsPoints

(mm Hg) if Untreated if Treated

<120 0 0120-129 1 3130-139 2 4140-159 3 5160 4 6

Step 4: Systolic Blood Pressure

Step 5: Smoking StatusNonsmoker 0 0 0 0

0Smoker 9 7 4 2

1

Age

Total cholesterol

HDL-cholesterol

Systolic blood pressure

Smoking status

Point total

Step 6: Adding Up the Points

Step 7: CHD Risk

Step 2: Total Cholesterol

ATP III Framingham Risk Scoring

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Recommendations for Noninvasive Screening

• AHA Prevention V (Greenland et al., Circ. 2000) indicated persons at intermediate risk may be suitable for screening by noninvasive tests, including ABI and carotid US for those over age 50 years, and coronary calcium screening.

• ATP III has suggested CAC scores above 75th percentile indications for more aggressive treatment (e.g., as CHD risk equivalent).

Cardiovascular Health Study: Combined intimal-medial thickness

predicts total MI and stroke

Cardiovascular Health Study (CHS) (aged 65+): MI or stroke rate 25% over 7 years in those at highest quintile of combined IMT (O’Leary et al. 1999)

Significant Coronary Artery Calcium (Score >400)

Risk of Total Mortality by Calcium Category in 10,377 Asymptomatic IndividualsShaw LJ et al., Radiology 2003; 228: 826-33

L – Lifestyle Change: First Line of Defense Against Heart Disease

• The AHA expert panel rated the following as Class I recommendations:– Stop cigarette smoking and avoid secondhand tobacco smoke

– Get at least 30 minutes of physical activity most or preferably all days (60-90 minutes for those needing to lose or sustain weight)

– Start a risk-reduction or cardiac rehabilitation program if recent acute coronary syndrome or cardiovascular event

– Eat a heart-healthy diet (consistent with NCEP/ATP III TLC)

– Maintain healthy weight by balancing caloric intake with caloric expenditure to achieve BMI between 18.5-24.9 kg/m2

Mosca et al. Circulation 2004 and 2007

Other Recommendations • The following are Class II recommendations:

– Omega-3 fatty acids (850-1000 mg EPA and DHA per day) may be considered in women with CHD, higher doses in those with high TG

– Consider screening women with CHD for depression and refer/treat where indicated

ATP III: Nutritional Components of the TLC Diet

Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

*Trans fatty acids also raise LDL-C and should be kept at a low intake.Note: Regarding total calories, balance energy intake and expenditure tomaintain desirable body weight.

<200 mg/dCholesterol

~15% of total caloriesProtein

20–30 g/dFiber

50%–60% of total caloriesCarbohydrate (esp. complex carbs)

25%–35% of total caloriesTotal fat

Up to 20% of total caloriesMonounsaturated fat

Up to 10% of total caloriesPolyunsaturated fat

<7% of total caloriesSaturated fat*

Recommended IntakeNutrient

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Possible Benefits From Other Therapies

Therapy Result

• Soluble fiber in diet (2–8 g/d) (oat bran, fruit, and vegetables)

• Soy protein (20–30 g/d)

• Stanol esters (1.5–4 g/d) (inhibit cholesterol absorption)

• Fish oils (3–9 g/d) (n-3 fatty acids)

LDL-C 1% to 10%

LDL-C 5% to 7%

LDL-C 10% to 15%

Triglycerides 25% to 35%

Jones PJ. Curr Atheroscler Rep. 1999;1:230-235.Lichtenstein AH. Curr Atheroscler Rep. 1999;1:210-214.Rambjor GS et al. Lipids. 1996;31:S45-S49.Ripsin CM et al. JAMA. 1992;267:3317-3325.

Nuts, Soy, Phytosterols, Garlic• Nurses’ Health Study: five 1oz servings of nuts per week

associated with 40% lower risk of CHD events; 2-4 servings/wk 25% lower risk

• Metaanalysis of 38 trials of soy protein showed 47g intake lowered total, LDL-C, and trigs 9%, 13%, and 11%, respectively; no effect on HDL-C.

• Phytosterol-supplemented foods (e.g., stanol ester margarine) lowers LDL-C avg. 10%

• Meta-analysis of garlic studies showed 9% total cholesterol reduction from 1/2-1 clove consumed daily for 6 months.

BMI and Relative Risk of CHD Over 14 Years: Nurse’s Health Study

• Relative risk of CHD increases for BMI > 23, diabetes risk increases for BMI > 22.

• Risk also significantly increases for weight gain after age 18 years of 5 kg or more. 0

0.5

1

1.5

2

2.5

3

3.5

<21 21-22.9 23-24.9 25-28.9 >29

Health Benefits of Weight Loss

• Decreased cardiovascular risk

• Decreased glucose and insulin levels

• Decreased blood pressure

• Decreased LDL and triglycerides, increased HDL

• Decrease in severity of sleep apnea

• Reduced symptoms of degenerative joint disease

• Improved gynecological conditions

National Obesity Education Initiative Treatment

Algorithm

Patient Encounter

Hx of 25 BMI?

•Measure weight, height, and waist circumference •Calculate BMI

Examination

Brief reinforcement/ educate on weight management

Periodic weight check

Advise to maintain weight/address other risk factors

Clinician and patient devise goals and treatment strategyfor weight loss andrisk factor control

Assess reasons for failure to lose weight

Maintenance counseling: Dietary therapy Behavior therapy Physical activity:

Treatment

Assess risk factors

No

Yes

1

2

14

15 13

12

11 1016

3

4 6

5 7

8

9

Yes

No

Yes

No

Hx BMI 25?

No

Yes

Yes

No

Does patient want to lose weight?

Yes

No

Progress being made/goal

achieved?

BMI 25 OR waist circumference

> 88 cm (F) > 102 cm (M)

BMI 30 OR

{[BMI 25 to 29.9 OR waist circumference

>88 cm (F) >102 cm (M)] AND 2 risk

factors}

BMImeasured in past

2 years?

Whenever possible, weight loss therapy should employ the combination of

• Low-calorie/low-fat diets

• Increased physical activity

• Behavior modification

Weight Loss Therapy

O – Other Major Risk Factor Interventions with Class I

Recommendations (Mosca et al. 2007)

• Blood pressure • Lipids• Diabetes• Aspirin• Beta-blockers (all women after MI, ACS, LV

dysfunction)• ACE inhibitors/ ARBS – MI, CHF, DM• Aldosterone blockage – post MI with CHF

Blood Pressure

• Encourage optimal BP of <120/80 mmHg through lifestyle approaches

• Pharmacotherapy when BP >=140/90 (or 130/80 if DM or CKD). Thiazide diuretics part of therapy for most pts. High risk women initially treated with beta blockers and/or ACE-I/ARB with addition of other drugs including diuretics to achieve goal

Blood Pressure Classification

Normal <120 and <80

Prehypertension 120–139 or 80–89

Stage 1 HTN 140–159 or 90–99

Stage 2 HTN >160 or >100

BP Classification SBP mmHg

DBP mmHg

4-Year Progression To Hypertension: The Framingham Heart Study

5

18

37

0

10

20

30

40

50

Optimal Normal High-Normal

Pat

ien

ts (

%)

(<120/80 mm Hg)

(130/85 mm Hg) (130-139/85-89 mm

Hg)Vasan, et al. Lancet 2001;358:1682-86

Participants age 36 and older

JNC-7 New Features and Key Messages

Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes.

Certain high-risk conditions are compelling indications for other drug classes.

Most patients will require two or more antihypertensive drugs to achieve goal BP.

If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.

I have some bad news for you. While your cholesterol has remained the same, the research

findings have changed.

Total Cholesterol Distribution: CHD vs Non-CHD Population

Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.1996 Reprinted with permission from Elsevier Science.

35% of CHD 35% of CHD Occurs in Occurs in People with People with TC<200 mg/dLTC<200 mg/dL

150 200

Total Cholesterol (mg/dL)

250 300

No CHD

CHD

Framingham Heart Study—26-Year Follow-up

Accumulation of Other Risk Factors Compound Effects of Dyslipidemia on Risk of CHD

0

5

10

15

20

25

30

35

40

185 210 235 260 285 310 335

Low HDL

Smoking

Hyperglycemia

Hypertension

No Other Risk Factors

Schaefer EJ, adapted from the Framingham Heart Study

CH

D R

isk

Per

100

0 (i

n 6

yea

rs)

Serum Cholesterol (mg/dL)

Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal (Framingham)

Risk of CHD by HDL-C and Total-C levels; aged 48–83 yCastelli WP et al. JAMA 1986;256:2835–2838

02468

101214

< 40 40–49 50–59 60< 200

230–259200–229

260

HDL-C (mg/dL) Tota

l-C (m

g/dL

)

14

-y in

cid

en

ce

rate

s (%

) fo

r C

HD

11.24

11.91

12.50

11.91

6.56

4.67

9.05

5.53

4.85

4.153.77

2.782.06

3.83

10.7

6.6

Adapted from Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q.

Primary and Secondary Prevention Trials With Statins

2° prevention placebo

2° prevention statin

1° prevention placebo

1° prevention statin

0

5

10

15

20

25

30

80 90 100 110 120 130 140 150 160 170 180 190 200

LDL-C Achieved (mg/dL)

AFCAPS

AFCAPS

WOSCOPS

WOSCOPS

CARECARE

LIPID LIPID

4S

4S

Eve

nt

Rat

e (%

)

HPSHPS

Statin Trials: Therapy Reduces Major Coronary Events in Women

n = number of women enrolled.* 4S = primarily CHD death and nonfatal MI;

CARE = coronary death, nonfatal MI, angioplasty, or bypass surgery;AFCAPS/TexCAPS = fatal/nonfatal MI, unstable angina, or sudden cardiac death.

Miettinen TA et al. Circulation. 1997;96:4211-4218.Lewis SJ et al. J Am Coll Cardiol. 1998;32:140-146.Downs JR et al. JAMA. 1998;279:1615-1622.

4S (n=827) CARE (n=576) AFCAPS/TexCAPS (n=997)

2 Prevention 1 Prevention

-50-45-40-35-30-25-20-15-10-505

10

Major coronary events*

-34

-46 -46

%

P=0.012

P=0.001

MRC/BHF Heart Protection Study (HPS): Eligibility

• Age 40–80 years

• Increased risk of CHD death due to prior disease

– Myocardial infarction or other coronary heart disease

– Occlusive disease of noncoronary arteries

– Diabetes mellitus or treated hypertension

• Total cholesterol > 3.5 mmol/L (> 135 mg/dL)

• Statin or vitamins not considered clearly indicated or contraindicated by patient’s own doctors

Heart Protection Study Group. Lancet. 2002;360:7-22.

HPS: First Major Coronary Event

0.4 0.6 0.8 1.0 1.2 1.4

Nonfatal MI

Coronary death

Subtotal: MCE

Coronary

Noncoronary

Subtotal: any RV

Any MVE

Coronary events

Revascularizations

Type of Major Vascular Event

Statin-Allocated

(n = 10269)

Placebo-Allocated

(n = 10267)

357 (3.5%) 574 (5.6%)

587 (5.7%) 707 (6.9%)

898 (8.7%) 1212 (11.8%)

513 (5.0%) 725 (7.1%)

450 (4.4%) 532 (5.2%)

939 (9.1%) 1205 (11.7%)

2033 (19.8%) 2585 (25.2%)

0.73 (0.670.79)P < 0.0001

0.76 (0.700.83)P < 0.0001

0.76 (0.720.81)P < 0.0001

Statin Better Placebo Better

Heart Protection Study Collaborative Group. Lancet. 2002;360:722.

HPS—Simvastatin: Vascular Events by Baseline

LDL-C

Baseline

LDL-C (mg/dL)Statin

(n = 10,269)Placebo

(n = 10,267)

<100 282 (16.4%) 358 (21.0%)

100–129 668 (18.9%) 871 (24.7%)

130 1083 (21.6%) 1356 (26.9%)

All patients 2033 (19.8%) 2585 (25.2%)

Event Rate Ratio (95% CI)Statin Better Statin Worse

0.4 0.6 0.8 1.0 1.2 1.4

www.hpsinfo.org

0.76 (0.72–0.81)P < 0.0001

0

20

40

60

80

100

120

140

160 Atorvastatin 10 mg (n=5006)

Atorvastatin 80 mg (n=4995)

TNT: Changes in LDL-C by Treatment Group

TNT: Changes in LDL-C by Treatment Group

FinalFinalScreenScreen 00 33 1212 2424 3636 4848 6060

PP<.001<.001

BaselineBaseline

4.04.0

3.53.5

3.03.0

2.52.5

2.02.0

1.51.5

1.01.0

0.50.5

00

Mean

LD

L-C

(mm

ol/L

)M

ean L

DL

-C (m

mo

l/L)

Mean LDL-C level = 101 mg/dL (2.6 mmol/L)Mean LDL-C level = 101 mg/dL (2.6 mmol/L)

Mean LDL-C level = 77 mg/dL (2.0 mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L)

LaRosa et al. LaRosa et al. N Engl J Med.N Engl J Med. 2005;352:1425-1435. 2005;352:1425-1435.

Mea

n L

DL

-C (

mg

/dL

)M

ean

LD

L-C

(m

g/d

L)

Study Visit (Months)Study Visit (Months)

TNT: Primary Efficacy Outcome Measure: Major Cardiovascular Events*

** CHD death, nonfatal nonCHD death, nonfatal non––procedure-related MI, resuscitated cardiac arrest, procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.fatal or nonfatal stroke.LaRosa et al. LaRosa et al. N Engl J Med.N Engl J Med. 2005;352:1425-1430. 2005;352:1425-1430.

HR=0.78 (95% CI 0.69, 0.89); HR=0.78 (95% CI 0.69, 0.89); PP<.001<.001

Pro

po

rtio

n o

f P

atie

nts

Exp

erie

nci

ng

P

rop

ort

ion

of

Pat

ien

ts E

xper

ien

cin

g

Maj

or

Car

dio

vasc

ula

r E

ven

tM

ajo

r C

ard

iova

scu

lar

Eve

nt

00

0.050.05

0.100.10

0.150.15

Atorvastatin 10 mgAtorvastatin 10 mg

Atorvastatin 80 mgAtorvastatin 80 mg Relative Relative risk risk

reduction reduction

22% 22%

00 11 22 33 44 55 66Time (Years)Time (Years)

Mean LDL-C level = 77 mg/dL Mean LDL-C level = 77 mg/dL

Mean LDL-C level = 101 mg/dL Mean LDL-C level = 101 mg/dL

Cholesterol Treatment Trialists’ (CCT) Collaboration: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis fo data from 90,056 participants in 14 randomized

trials of statins (The Lancet 9/27/05)

• Over average 5 year treatment period (per mmol/L reduction—approx 40 mg/dl in LDL-C):– 12% reduction in all-cause mortality– 19% reduction in coronary mortality– 23% reduction in MI or CHD death– 17% reduction in stroke– 21% reduction in major vascular events– No difference in cancer incidence (RR=1.00).

• Statin therapy can safely reduce 5-year incidence of major coronary events, revascularization, and stroke by about 20% per mmol/L (about 38 mg/dl) reduction in LDL-C

Lipid Management (Mosca et al., 2007)

• Encourage through lifestyle approaches:– LDL-C <100 mg/dl, HDL-C >50 mg/dl, triglycerides <150 mg/dl,

and non-HDL-C <130 mg/dl

• In high risk women, utilize LDL-C lowering drug therapy to achieve LDL-C <100 mg/dl, with an optional reduction to <70 mg/dl in very-high-risk women with CHD

• For other at-risk women, utilize LDL-C lowering drug therapy with lifestyle therapy according to NCEP ATP III when:– LDL-C >=130 mg/dl if multiple risk factors and 10-20% risk– LDL-C >=160 mg/dl if muliple risk factors and <10% risk– LDL-C >=190 mg/dl regardless of presence of other risk factors

Lipid Therapy (continued)

• Use niacin or fibrate therapy when HDL-C is low or non-HDL-C is elevated in high risk women after LDL-C goal is reached

• Consider niacin or fibrate therapy when HDL-C is low or non-HDL-C is elevated after LDL-C goal is reached in women with multiple risk factors and 10-year risk 10-20%

When LDL-lowering drug therapy When LDL-lowering drug therapy

is employed in high-risk or is employed in high-risk or

moderately high risk patients, moderately high risk patients,

intensity of therapy should be intensity of therapy should be

sufficient to achieve a 30–40% sufficient to achieve a 30–40%

reduction in LDL-C levels.reduction in LDL-C levels.

Grundy et al. Circulation. 2004;110:227-239.

Doses of Statins Required to Attain 30-40% Reduction of LDL-C

Dose, mg/dLDL Reduction,

%

Atorvastatin 10 39

Lovastatin 40 31

Pravastatin 40 34

Simvastatin 20-40 35-41

Fluvastatin 40-80 25-35

Rosuvastatin 5-10 39-45

Questran® Prescribing Information, Colestid ® Prescribing Information, WelChol ® Prescribing information, Niaspan ® Prescribing Information, Lopid ® Prescribing Information, TriCor ® Prescribing Information, Lipitor ® Prescribing Information, Zocor ® Prescribing Information, Mevaco ® r Prescribing Information, Lescol ® Prescribing Information, Pravacol ® Prescribing Information; Zetia ® Prescribing Information.

Effect of Lipid-modifying Therapies

TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin.

Therapy TC LDL HDL TGPatient

tolerability

Bile acid sequestrants

7-10% 10-18% 3% Neutral or Poor

Nicotinic acid

10-20% 10-20% 14-35% 30-70%Poor to

reasonable

Fibrates (gemfibrozil)

19% 4-21% 11-13% 30% Good

Statins* 19-37% 25-50% 4-12% 14-29% Good

Ezetimibe 13% 18% 1% 9% Good

Diabetes Mellitus

• Lifestyle and pharmacotherapy should be used as indicated in women with diabetes to achieve an HbA1C <7%

• Insulin, metformin, TZDs, and DPP-4 inhibitors are important classes of drugs that aid in diabetes control

Diabetes as a CHD Risk Equivalent

• 10-year risk for CHD 20%• High mortality with established CHD

– High mortality with acute MI– High mortality post acute MI

Prevalence has increased over 25% in past 15 years in California, paralleling 50% increase in overweight/obesity

Collaborative Atorvastatin Diabetes Study (CARDS)

• 2838 patients aged 40-75 with type 2 diabetes, no prior CVD, but at least 1 of the following: retinopathy, albuminuria, smoking, or hypertension

• Randomization to 10 mg atorvastatin or placebo• Mean follow-up 3.9 years• Reduction in all CVD events of 37% (p=0.001),

all cause mortality 27% (p=0.059). CHD events reduced 36% and stroke 48%.

Colhoun HM et al., The Lancet 2004; 364: 685-696

Probability of Death From CHD in Patients With NIDDM and in Nondiabetic Patients,

With and Without Prior MI

Kaplan-Meier estimatesHaffner SM et al. N Engl J Med 1998;339:229–234

0 1 2 3 4 5 6 7 80

20

40

60

80

100

Nondiabetic subjects without prior MI

Diabetic subjects without prior MI

Nondiabetic subjects with prior MI

Diabetic subjects with prior MI

Years

Surv

ival (%

)

Framingham Heart Study 30-Year Follow-Up:CVD Events in Patients With Diabetes

(Ages 35-64)10

9

20

11

9 63819

3*

30

0

2

4

6

8

10

Age-adjusted annual rate/1,000

Men Women

Total CVD

CHD Cardiac failure

Intermittent claudication

Stroke

Riskratio

P<0.001 for all values except *P<0.05.

Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease.Ruderman N et al, eds. Oxford; 1992.

The Metabolic Syndrome

InsulinResistance

Hypertension

Type 2 Diabetes

DisorderedFibrinolysis

ComplexDyslipidemia

TG, LDL

HDL

EndothelialDysfunction

SystemicInflammation

Athero-sclerosis

VisceralObesity

Adapted from the ADA. Diabetes Care. 1998;21:310-314;Pradhan AD et al. JAMA. 2001;286:327-334.

ATP III: The Metabolic Syndrome*

*Diagnosis is established when 3 of these risk factors are present.†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡Some men develop metabolic risk factors when circumference is only marginally ; ** new ADA guideline for impaired fasting glucose >=100 mg/dlincreased.Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

<40 mg/dL<50 mg/dL

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

MenWomen

**100 mg/dLFasting glucose130/85 mm Hg or on medsBlood pressure

HDL-C150 mg/dLTG

Abdominal obesity† (Waist circumference‡)

Defining LevelRisk Factor

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www.lipidhealth.org

Cardiovascular Disease (CVD) and Total Mortality: US Men and Women Ages 30-74

(age, gender, and risk-factor adjusted Cox regression) NHANES II Follow-Up (n=6255)(Malik and Wong, et al., Circulation 2004; 110: 1245-1250)

0

1

2

3

4

5

6

7

CHD Mortality CVD Mortality Total Mortality

None

MetS

Diabetes

CVD

CVD+Diabetes

* p<.05, ** p<.01, **** p<.0001 compared to none

*

***

***

***

**

***

***

***

******

***

Aspirin

• Aspirin therapy (75 to 325 mg/d) should be used in high-risk women unless contraindicated or intolerated (where clopidogrel should be substituted)

• Other at risk or healthy women: for those aged >=65 consider aspirin therapy (81 mg daily or 100 mg every other day) if BP controlled and benefit for stroke/MI prevention is likely to outweigth GI bleeding/hemorrhagic stroke risk.

H – Highest Priority for Therapy is for Women at Highest Risk

• Those at highest risk, who already have pre-existing CVD, diabetes, or chronic kidney disease are most likely to benefit from preventive therapy involving the following Class I recommendations:– ACE inhibitor therapy (if coughing, subst. ARB)– Aspirin therapy (baby aspirin or maximum dose of 162 mg)

unless contraindicated– Beta-blocker therapy in those with prior MI or current angina– Statin therapy – Niacin or fibrate therapy if low HDL present– Fibrates to lower triglycerides and improve HDL– Warfarin in those with atrial fibrillation unless

contradindicated

A – Avoid “Class III” Interventions(Not proven useful or effective / may be harmful)

• Combined estrogen and progestin therapy, and *estrogen monotherapy since associated with increased risk of CVD

• Selective estrogen-receptor modulators (SERMs) also not recommended

• Antioxidant supplements including vigtamin E, C, and beta-carotene

• Folic acid with or without B6 or B12 supplementation• Aspirin for MI prevention in women aged <65 years

Vitamins: Major Vascular Events

Vascular Event

Major coronary 1063 1047

Any stroke 511 518

Revascularization 1058 1086

Any of the above 2306 (22.5%)

2312 (22.5%)

Heart Protection Study Collaborative Group. Lancet. 2002;360:23–33.

Risk Ratio and 95% CIRisk Ratio and 95% CI

Vitamin BetterVitamin Better Vitamin WorseVitamin Worse

0.40.4 0.60.6 0.80.8 1.01.0 1.21.2 1.41.4

1.00 (0.94–1.06)P > 0.9

Vitamins (n = 10,269)

Placebo (n = 10,267)

Does Hormone Replacement Therapy Prevent Heart Disease

• Epidemiologic studies over the past several decades together have shown approximately a 50% lower risk in women randomized to estrogen replacement therapy vs. placebo

• Even the Nurses’ Health Study showed those on estrogen/progestin to have approximately a 60% lower risk of heart disease events

Heart and Estrogen/Progestin Replacement Study (HERS): Secondary Prevention of CHD in

Women

• Randomized, placebo-controlled trial of E/P therapy vs. placebo in 2763 women with CHD; average age 67 years

• Treatment was 0.625 mg CEE + 2.5 mg medroxyprogesterone daily for 4 years

• Primary endpoint: nonfatal MI and CHD death• Secondary endpoints: CABG, PTCA, unstable

angina, CHF, PVD, TIAJAMA 1998;280:605-613

JAMA 1998;280:605-613

HERS Results• No statistically significant difference between HRT

and placebo in both primary and secondary endpoints after 4 years.

• Within first year, greater incidence in CHD events in HRT group. In years 3 and 4, lower CHD events in HRT group compared to placebo.

• HRT lowered LDL 11% and increased HDL 10% compared to placebo.

• Approximately 50% of randomized women were on lipid-lowering drugs.

• Higher incidence of VTE and cholelithiasis in HRT group.

More Bad News: The Women’s Health Initiative

• Over 160,000 women nationwide, aged 50-79 and postmenopausal have participated in various components (observational, dietary modification, and HRT clinical trials)—over 3,000 at UCI

• The Estrogen/Progestin component of the HRT clinical trial involving 16,608 women nationwide was discontinued prematurely in Spring 2002 after 5.2 years of follow-up (instead of 8.5 years).

WHI Estrogen/Progestin and Estrogen Only Results

• Those randomized to estrogen/progestin compared to placebo and statistically significant increased risks:– Breast cancer 26% (8/10,000 person years)– Total coronary heart disease 29% (7/10,000 person years)– Stroke 41% (8/10,000 person years)– Pulmonary emobolism 2.1 X (8/10,000 person years)– Protective for colorectal cancer (37% lower) and hip fracture

(34% lower): no effect endometrial cancer or total mortalityJAMA. 2002 Jul 17;288(3):321-33.

• Estrogen-only arm was also recently discontinued in December 2003 and was associated with a 39% increased risk of stroke (12 excess strokes per 10,000 person years) and 12% significant increased risk of cardiovascular events. JAMA. 2004 Apr 14;291(14):1701-12.

For More Information about Preventing Heart Disease:

Preventive Cardiology, 2nd ed.from McGraw-Hill …..

For more information, see the UCI Heart Disease Prevention Website at www.heart.uci.edu