Lipids and Cardiovascular Disease Prevention

1
Lipids and Cardiovascular Disease Prevention

• Epidemiology
• Clinical Trials Evidence
• Dietary and Pharmacologic Management

Nathan Wong
2
Cholesterol and CHD Seven Countries Study
Northern Europe United States Southern Europe,
Inland Southern Europe, Mediterranean Siberia Japa
n
30
25
20
CHDmortality rates()
15
10
5
0
100
125
150
175
200
225
250
275
300
325
350
(2.60)
(3.25)
(3.90)
(4.50)
(5.15)
(5.80)
(6.45)
(7.10)
(7.75)
(8.40)
(9.05)
TC mg/dL (mmol/L)
Verschuren WMM et al. JAMA. 1995274131-136.
3
Effects of Increasing TC Levels on the Risk for
CHD in the Presence of Other Risk Factors
Low HDL
Smoking
CHD Risk Per 1000 (in 6 years)
Hyperglycemia
Hypertension
No Other Risk Factors
Serum Cholesterol (mg/dL)
Schaefer EJ, adapted from the Framingham Heart
Study
4
Total Cholesterol Distribution CHD vs Non-CHD
Population
Framingham Heart Study26-Year Follow-up
No CHD
35 of CHD Occurs in People with TClt200 mg/dL
CHD
150
250
300
200
Total Cholesterol (mg/dL)
Adapted from Castelli WP. Atherosclerosis.
1996124(suppl)S1-S9.
5
HDL-C Distribution in US Adults
16
14
12
10
No. of US adults (millions)
8
6
4
2
0
? 2 RF, no CHD
lt 35
35lt 45
CHD
45lt 60
? 60
HDL-C (mg/dL)
RF risk factors Data from NHANES III, 19881994
6
CHD Risk According to HDL-C LevelsFramingham
Study
4.0
4.0
3.0
CHD risk ratio
2.0
2.0
1.0
1.0
0
65
25
45
HDL-C (mg/dL)
Kannel WB. Am J Cardiol 1983529B12B
7
Wine Consumption and CHD
CHD -4.99W 652.4 r -0.580
8
CHD Risk According to HDL-C LevelsProspective
Cardiovascular Münster Study
110
120
186 events in 4,407 men (aged 4065 y)
100
80
Incidence per 1,000 (in 6 years)
60
30
40
21
20
0
lt 35
3555
gt 55
HDL-C (mg/dL)
Assmann G, ed. Lipid Metabolism Disorders and
Coronary Heart Disease. Munich MMV Medizin
Verlag, 1993
9
Low HDL-C Levels Increase CHD Risk Even When
Total-C Is Normal
12.50
11.91
11.91
14
9.05
10.7
11.24
12
6.6
10
5.53
3.83
8
14-y incidence rates () for CHD
6.56
4.85
6
? 260
4.67
2.06
4.15
3.77
4
2.78
230259
2
200229
Total-C (mg/dL)
0
lt 200
lt 40
4049
5059
? 60
HDL-C (mg/dL)
Risk of CHD by HDL-C and Total-C levels aged
4883 y Castelli WP et al. JAMA 198625628352838
10
Hypertriglyceridemia Increases CHD Risk in
Patients with Low HDL-C LevelsProspective
Cardiovascular Munster Study

250
TG lt 200 mg/dL TG ? 200 mg/dL
245
200
150
Incidence per 1,000 (in 6 years)
116
100
50
31
24
0
? 5.0
gt 5.0
LDL-C/HDL-C ratio
Bar represents 5 of subjects in which 25 of
CHD events occurred.
11
Distribution of HDL-C Levels in Men With
CHDVA-HIT Study Group

• HDL-C level Whites Blacks All subjects
• (mg/dL) (n 2,891) (n 572) (n 8,578)
• lt 35 42 20 38
• 3540 25 23 25
• gt 40 32 57 36

63
Rubins HB et al. Am J Cardiol 19957511961201
12
CHD Incidence Related to HDL-C Levels in Various
Trials
CHD incidence
Men
Women
0
-2
change in risk per 1 mg/dL increment in HDL-C
-4
-6
-8
-10
FHS
FHS
CPPT
LRCF
LRCF
MRFIT
13
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, 19881994 (unpublished data) 2.
Mahley RW et al. J Lipid Res 199536839859
14
Ethnic Variations in Lipid Parameters Insulin
Resistance Atherosclerosis Study

• African- Non-Hispanic
• Americans Hispanics Whites P value
• n 462 (27) 546 (34) 612 (38) lt 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 lt 0.001
• TG (mg/dL) 102.1 147.7 134.0 lt 0.001

Haffner SM et al. Arterioscler Thromb Vasc Biol
19991922342240.
15
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

16
Lp(a) An Independent CHD Risk Factor in Men of
the Framingham Offspring Cohort
10
5
3.6
2.7
2
1.9
1.8
1.8
1.2
1
RR
0.5
Lp(a) TC HDL-C HT GI Smoking
0.2
0.1
RRrelative risk HThypertension GIglucose
intolerance. Bostom AG et al. JAMA.
1996276544-548.
17
Lipid ManagementClinical Trial Data
18
Effect of Lifestyle Changeson Angiographic CAD
Duration
(Control-Treatment)

Study
N
Patient type
Therapy
(yr)
Progression
Regression
Lifestyle
28
CAD
Diet,
exercise,
1
35
-40
meditation
STARS
90
CAD, high
TC
Diet (including
3.2
35
-38

fiber)
Heidelberg
113
CAD
Diet exercise
1
25
-15
19
Early Primary-Prevention Trials Overview
Oslo Diet/smoking cessation N1,232, P0.02
TC
CHD events
0
-5
WHO ClofibrateN15,745, Plt0.05
-10
-8.5
-9
-9
-11
-15
-14
Upjohn ColestipolN2,278, P0.02
-20
-19
-20

-25
-23
LRC-CPPT CholestyramineN3,806, Plt0.05
-30
-35
-34
-40
HHS Gemfibrozil N4,081, Plt0.02
-45
-47
-50
Nnumber enrolled.
Net difference between treatment and control
groups (P values are for events).
20
Early Secondary-Prevention Trials Overview
TC
CHD events
CDP Clofibrate (n1,103)N8,341, Pns
CDP Niacin (n1,119)N8,341, Pns
Stockholm Clofibrate niacinN555, Pns

POSCH Partial ileal bypassN838, Plt0.001
Nnumber enrolled nsnot significant.
Net difference between treatment and control
groups (P values are for events).
21
Summary of Effects of Lipid Lowering on Lipids
and Clinical Events in Recent Statin Trials
Nonfatal MI/CHD death
8
10
CHD death
All-cause mortality
5
5
5
LDL-C
TC
0
HDL-C
-5
-10
-9

-15
-20
-20
-20
-20
-22
-25
-24
-25
-26
-30
-28
-30
-31
-35
-33
-34
-35
-40
-42
-45
WOSCOPS (N6,595)
4S (N4,444)
CARE (N4,159)
1o prevention
2o prevention
2o prevention
Nnumber enrolled.
22
WOSCOPS Effects of Lipid Lowering on Coronary
Events in Primary Prevention Trial in Men
Nonfatal MI/CHD death
10
CHD death
All-cause mortality
5
5
TC
LDL-C
0
HDL-C
-5
-10

-15
-20
-20

-25
-22
-26
-30

-35
-31
-33
Plt0.0005. P0.042. P0.051.
Shepherd J et al. N Engl J Med.
19953331301-1307.
23
WOSCOPS Relation of Baseline LDL-C to Event Rate
5-year event rate (per 100)
WOSCOPS Group. Circulation. 1998971440-1445.
24
4S Effect of LDL-C Lowering on Coronary Events
in Secondary Prevention Trial
Nonfatal MI/CHD death
8
10
All-cause mortality
CHD death
5
TC
LDL-C
0
HDL-C
-5
-10
-15

-20
-25
-25
-30
-30
-35

-34
-35
-40
-45
-42
Plt0.00001. 95 CI -27 to -54. P0.003.
4S Group. Lancet. 19943441383-1389.
25
4S Effects of Cholesterol Lowering on
Noncoronary Ischemic Symptoms and Angina
Intermittent Claudication
Carotid Bruit
Fraction of patients
Months
Months
Angina
Cerebrovascular Events
Fraction of patients
Months
Months
Simvastatin Placebo
26
4S Lipid Lowering Reduces CHD Event Rates in
³65-Year-Old Subjects
P0.009
P0.003
P0.003
Percent of patients
Total mortality
Coronary mortality
Revascularization
27
4S Clinical and Economic Benefits of Treatment
Over 5-Yr Period
Cost of simvastatin therapy
Hospital days
Major CHD events
Hospital costs
LDL-C
0
-20

-31

-40
-34
-34
-35

-60
-80

-88
-100
LDL-C
CHD events
Admissions
Net cost of therapy
Plt0.0001.Translates to savings of
3,872/patient.Translates to cost of 0.28/day.
28
LIPID Effect of Lipid Lowering on Lipid Values
and Coronary Events in CHD Patients With Average
Cholesterol
5
NonfatalMI/CHDdeath
CHDdeath
All-causemortality
TC
LDL-C
HDL-C
Plt0.001
-18
-22
-24
-24
-25
LIPID Study Group. N Engl J Med.
19983391349-1357.
29
LIPID Reduction in Nonfatal MI and CHD Death
Risk Stratified by Age at Baseline
lt55 55-64 65-69 ?70
0
10

-15
20
-20
-28
30
-32
40
Age
LIPID Study Group. N Engl J Med.
19983391349-1357.