Lipids and Cardiovascular Disease Prevention

•Epidemiology

•Clinical Trials Evidence

•Dietary and Pharmacologic Management

Nathan Wong

0

5

10

15

20

25

30

(2.60) (3.25)(3.90)(4.50) (5.15) (5.80)(6.45) (7.10) (7.75) (8.40)(9.05)

Cholesterol and CHD: Seven Countries Study

TC mg/dL (mmol/L)

CHDmortality rates

(%)

Verschuren WMM et al. JAMA. 1995;274:131-136.

100 125 150 175 200 225 250 275 300 325 350

Northern EuropeUnited StatesSouthern Europe, InlandSouthern Europe, MediterraneanSiberiaJapan

Effects of Increasing TC Levels on the Risk for CHD in the Presence of Other Risk Factors

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)

Total Cholesterol Distribution: CHD vs Non-CHD Population

Adapted from Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.

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

HDL-C Distribution in US Adults

RF = risk factorsData from NHANES III, 1988–1994

HDL-C (mg/dL)

< 35 35–< 45 45–< 60 60CHD

02468

10

121416

2 RF, no CHD

No. o

f US

adul

ts (m

illion

s)

CHD Risk According to HDL-C LevelsFramingham Study

4.0

3.0

2.0

1.0

25 45 65HDL-C (mg/dL)

CH

D r

isk

rati

o

Kannel WB. Am J Cardiol 1983;52:9B–12B

2.0

1.0

0

4.0

Wine Consumption and CHDCHD = -4.99W + 652.4

r = -0.580

0 20 40 60 80 100

Finland

U.S.Australia

New ZealandIrelandU.K.

CanadaDenmarkNorway

Sweden

NetherlandsW. Germany Belgium Austria

Japan

Switzerland Italy

France

Wine, liter/capita-year

Mortality rate

1000

800

600

400

200

CHD Risk According to HDL-C LevelsProspective Cardiovascular Münster Study

110

3021

0

20

40

60

80

100

120

< 35 35–55 > 55

Inci

den

cep

er

1,0

00

(in

6 y

ears

)

HDL-C (mg/dL)

Assmann G, ed. Lipid Metabolism Disorders and Coronary Heart Disease. Munich: MMV Medizin Verlag, 1993

186 events in 4,407 men (aged 40–65 y)

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

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

Hypertriglyceridemia Increases CHD Risk in Patients with Low HDL-C Levels

Prospective Cardiovascular Munster Study

* Bar represents 5% of subjects in which 25% of CHD events occurred.

24 31

116

245

0

50

100

150

200

250

5.0 > 5.0

*

LDL-C/HDL-C ratio

Inci

den

cep

er

1,0

00

(in

6 y

ears

)TG < 200 mg/dL

TG 200 mg/dL

Distribution of HDL-C Levels in Men With CHD

VA-HIT Study Group

HDL-C level Whites Blacks All subjects (mg/dL) (n = 2,891) (n = 572) (n = 8,578)

< 35 42% 20% 38%

35–40 25% 23% 25%

> 40 32% 57% 36%

Rubins HB et al. Am J Cardiol 1995;75:1196–1201

}63%

CHD Incidence Related to HDL-C Levels in Various Trials

% c

han

ge in r

isk

per

1

mg

/dL

incr

em

en

t in

HD

L-C

0

-2

-4

-6

-8

-10

FHSLRCF

CPPTMRFIT

FHSLRCF

CHD incidence

Men Women

Population, Gender, and Ethnic Variability in HDL-C Levels

Mean HDL-C level (mg/dL)

Population Men Women

United States (NHANES III)1

Whites 44 54

African-Americans

51 55

Turkey (Turkish Heart Study)2

37 42

1. NHANES III, 1988–1994 (unpublished data)2. Mahley RW et al. J Lipid Res 1995;36:839–859

Ethnic Variations in Lipid Parameters

Insulin Resistance Atherosclerosis Study African- Non-HispanicAmericans Hispanics Whites P value

n 462 (27%) 546 (34%) 612 (38%) < 0.001

Total-C (mg/dL) 212.5 211.1 213.2 0.782

LDL-C (mg/dL) 143.8 139.4 140.7 0.410

HDL-C (mg/dL) 47.0 42.3 44.0 < 0.001

TG (mg/dL) 102.1 147.7 134.0 < 0.001

Haffner SM et al. Arterioscler Thromb Vasc Biol 1999;19:2234–2240.

Lp(a) in Atherogenesis: Another Culprit?

• Identical to LDL particle except for addition of apo(a)

• Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although not all

• Accumulates in atherosclerotic plaque

• Binds apo B-containing lipoproteins and proteoglycans

• Taken up by foam cell precursors

• May interfere with thrombolysis

Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort

RR=relative risk; HT=hypertension; GI=glucose intolerance.

Bostom AG et al. JAMA. 1996;276:544-548.

1.9 1.8 1.81.2

2.73.6

RR

0.1

1

10

2

5

0.2

0.5 Lp(a) TC HDL-C HT GISmoking

Lipid Management:Clinical Trial Data

Effect of Lifestyle Changeson Angiographic CAD

Study N Patient type Therapy

Duration

(yr)

% (Control-Treatment)

Progression Regression

Lifestyle 28 CAD Diet, exercise,meditation

1 35 -40

STARS 90 CAD, high TC Diet (including fiber)

3.2 35 -38

Heidelberg 113 CAD Diet + exercise 1 25 -15

Superko HR, Krauss RM. Circulation . 1994;90:1056-1069.

-9

-47

-9

-20

-14

-23

-8.5

-19

-11

-34

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

%+

* Net difference between treatment and control groups (P values are for events).

TC * CHD events *

N=number enrolled.

Early Primary-Prevention Trials: Overview

WHO: ClofibrateN=15,745, P<0.05

Oslo: Diet/smoking cessation N=1,232, P=0.02

Upjohn: ColestipolN=2,278, P0.02

LRC-CPPT: CholestyramineN=3,806, P<0.05

HHS: Gemfibrozil N=4,081, P<0.02

Early Secondary-Prevention Trials: Overview

* Net difference between treatment and control groups (P values are for events).

N=number enrolled; ns=not significant.

-6-9-10

-13-13

-29

-23

-35

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0TC * CHD events *

CDP: Niacin (n=1,119)N=8,341, P=ns

CDP: Clofibrate (n=1,103)N=8,341, P=ns

Stockholm: Clofibrate + niacinN=555, P=ns

POSCH: Partial ileal bypassN=838, P<0.001

%+

-20

-26

5

-31-33

-22-25

-35

8

-34

-42

-30

-20

-28

5

-24

-20

-9

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

WOSCOPS (N=6,595) 4S (N=4,444) CARE (N=4,159)

N=number enrolled.

TC LDL-C

HDL-C

1o prevention

2o prevention

2o prevention

Summary of Effects of Lipid Lowering on Lipids and Clinical Events in Recent Statin

TrialsNonfatal MI/CHD death

CHD death

All-cause mortality

%+

-20

-26

5

-33

-22

-31*-35

-30

-25

-20

-15

-10

-5

0

5

10

Shepherd J et al. N Engl J Med. 1995;333:1301-1307.

* P<0.0005.† P=0.042.‡ P=0.051.

†

TC LDL-C

HDL-C

Nonfatal MI/CHD death

CHD death

All-cause mortality

WOSCOPS: Effects of Lipid Lowering on Coronary Events in Primary Prevention Trial in Men

‡

%+

0

2

4

6

8

10

12

14

170 182 190 200 220

Baseline LDL-C (mg/dL)

PlaceboPravastatin

5-year

event rate

(per 100)

WOSCOPS Group. Circulation. 1998;97:1440-1445.

WOSCOPS: Relation of Baseline LDL-C to Event Rate

4S Group. Lancet. 1994;344:1383-1389.

*P<0.00001.†95% CI: -27 to -54. ‡P=0.003.

4S: Effect of LDL-C Lowering on Coronary Events in Secondary Prevention Trial

-25

-35

8

-42 †

-30 ‡

-34

-45

-40

-35-30

-25

-20

-15

-10

-50

5

10

TC LDL-C

HDL-C

Nonfatal MI/CHD death

CHD death

All-cause mortality

%+

*

4S: Effects of Cholesterol Lowering on Noncoronary Ischemic Symptoms and Angina

Fra

ctio

n o

f p

ati

en

tsF

ract

ion

of

pa

tie

nts

0.0000.0050.0100.0150.0200.0250.0300.0350.0400.045

0 6 12 18 24 30 36 42 48 54 60 66 72Months Months

MonthsMonths

0.0000.0050.0100.0150.0200.025

0 6 1218 243036 4248 5460 6672

0.000.050.100.150.200.250.300.350.40

0 6 12 18 24 30 36 42 48 54 60 66 720.000.010.020.030.040.050.06

0 6 12 18 24 30 36 42 48 54 60 66 72

SimvastatinPlacebo

Intermittent Claudication Carotid Bruit

Angina Cerebrovascular Events

19.1

14.515.9

12.9

8.59.9

0

10

20

30

40Placebo (n=503)

Simvastatin (n=518)

Totalmortality

Coronarymortality

Revascularization

Percent of

patients

P=0.009 P=0.003 P=0.003

4S: Lipid Lowering Reduces CHD Event Rates in 65-Year-Old Subjects

-35 -34 -34 -31

-88-100

-80

-60

-40

-20

0

Cost of simvastatin

therapyLDL-C

Hospital days

Major CHD events

Hospital costs

*P<0.0001.†Translates to savings of $3,872/patient.‡Translates to cost of $0.28/day.

* †

LDL-C CHD events Admissions Net cost of therapy

‡

4S: Clinical and Economic Benefits of Treatment Over 5-Yr Period

%

+

LIPID: Effect of Lipid Lowering on Lipid Values and Coronary Events in CHD Patients With Average

Cholesterol

LIPID Study Group. N Engl J Med. 1998;339:1349-1357.

-25

-20

-15

-10

-5

0

5

10

TC LDL-C

NonfatalMI/CHDdeath

CHDdeath

All-causemortality

HDL-C

-18

-25 -24* -24*-22*

5

*P<0.001

LIPID: Reduction in Nonfatal MI and CHD Death Risk Stratified by Age at Baseline

-32

-20

-28

-15

40

30

20

10

0

Age

<55 55-64 65-69 70

LIPID Study Group. N Engl J Med. 1998;339:1349-1357.

%