lipids and cardiovascular disease prevention epidemiology clinical trials evidence dietary and...
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Lipids and Cardiovascular Disease Prevention
•Epidemiology
•Clinical Trials Evidence
•Dietary and Pharmacologic Management
Nathan Wong
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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
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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)
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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
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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)
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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
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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
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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)
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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
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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
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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%
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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
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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
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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.
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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
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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
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Lipid Management:Clinical Trial Data
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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.
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-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
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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
%+
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-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
%+
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-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
‡
%+
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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
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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
%+
*
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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
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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
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-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
%
+
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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
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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.
%