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Atherosclerosis
Diabetes
LIPOPROTEINS
Role Of Statins
CHD
Lipoproteins & Atherosclerosis
An Overview
Clinical Manifestations of Atherosclerosis
• Coronary heart disease
– Stable angina, acute myocardial infarction, sudden
death, unstable angina/NSTEMI
• Cerebrovascular disease
– Stroke, TIAs
• Peripheral arterial disease
– Intermittent claudication, amputation
L1-2
Normal arterial wall
Tunica adventitia
Tunica media
Tunica intima
Endothelium
Subendothelial connective
tissue
Internal elastic membrane
Smooth muscle cells
Elastic/collagen fibers
External elastic membrane
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Development of Atherosclerotic Plaques
Fatty streak
Normal
Lipid-rich plaque
Foam cells
Fibrous cap
Thrombus
Lipid core
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Deaths in 1996 (thousands)
Magnitude of the Burden—Causes of
Death in the United States
1,000
900
800
700
600
500
400
300
200
100
0
959.2
544.7
93.8
CVD
Cancer
Accidents
32.7
HIV/AIDS
American Heart Association. 1999 Heart and Stroke Statistical Update. 1998.L1-5
Risk Factors for CHD
• Modifiable
• Non-modifiable
– Dyslipidemia
– Family history of
premature CHD
– Age
– Sex
• Raised LDL
• Low HDL
• Raised TGs
–
–
–
–
–
–
–
Smoking
Hypertension
Diabetes mellitus
Obesity
Dietary factors
Thrombogenic factors
Sedentary lifestyle
Hypertension
(DBP >90 mm Hg)
x2.5
x3
Smoking
x3
x11
x7
x6
x3
Serum total cholesterol level
(>240 mg/dL
OR >6.2 mmol/L)
Adapted from Kannel WB, et al. Am Heart J. 1986;12:825-836.
L1-6
Relationship between Cholesterol
and CHD risk: The Framingham Study
CHD incidence per 1000
150
125
100
75
50
25
0
204
235265-294
295
264
Serum cholesterol (mg/100 mL)
205-234
mg/dL x 0.0259= mmol/L
Castelli WP. Am J Med. 1984;76:4-12.
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Cholesterol—a Modifiable Risk Factor
• 10% reduction in TC = 15% reduction in
CHD mortality and 11% reduction in total
mortality2
• LDL-C is the primary target to prevent
CHD3
• Intensity of intervention depends on total
CV risk3
1. AHA. 2000 Heart and Stroke Statistical Update.
2. Gould AL, et al. Circulation. 1998;97:946-952.
3. NCEP, Adult Treatment Panel II. JAMA. 1993;269:3015-3023.
L1-8
LDL cholesterol
• Remains the cornerstone of dyslipidemia therapy
• Strongly associated with atherosclerosis and
CHD events
• 10% increase results in a 20% increase in
CHD risk1
• Most patients with elevated LDL untreated
– Only 5.5 million out of 22 million treated2
1. Wood D, et al. Atherosclerosis. 1998;140:199-270.
2. National Centre for Health Statistics. National Health and Nutrition Examination Survey (III) 1994.L1-9
HDL cholesterol
• Elevated HDL cholesterol has a protective effect for
risk of atherosclerosis and CHD1
• The lower the HDL cholesterol level the higher
the risk for atherosclerosis and CHD1
• HDL cholesterol tends to be low when triglycerides
CHD Risk According to HDL-C
are high2
1. NCEP, Adult Treatment Panel II. JAMA. 1993;269:3015-3023.
2. Wood D, et al. Atherosclerosis. 1998;140:199-270.
3. Kannel WB. Am J Cardiol 1983;52:9B–12B
Levels
CHD risk ratio
• Risk assessment
– Routinely measured in all adult patients
– HDL-C <0.9 mmol/L is a major positive
risk factor
– HDL-C 1.55 mmol/L is a negative
risk factor;
subtract 1 risk factor from total
4.
0
3.
0
2.
0
1.
0
0
4.0
Framingham Study3
2.0
1.0
25 45 65
HDL-C (mg/dL)
mg/dL x 0.0259= mmol/L
L1-10
Triglycerides
• Associated with increased risk of CHD events
• Link with increased CHD risk is complex
– May be related to low HDL levels and highly
atherogenic forms of LDL cholesterol
• Normal triglyceride levels <2.26 mmol/L
• Very high triglycerides (>11.3 mmol/L) increase
pancreatitis risk
NCEP, Adult Treatment Panel II. JAMA. 1993;269:3015-3023.
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National Cholesterol Education
Program, (NCEP) Reports
• Adult Treatment Panel I (1988)
Adult Treatment Panel II (1993)
Adult Treatment Panel III (2001)
• Recommendations for Improving Cholesterol
Measurement (1990)
Recommendations on Lipoprotein Measurement (1995)
• Population Strategies for Blood Cholesterol Reduction
(1990)
• Blood Cholesterol Levels in Children and Adolescents
(1991)
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ATP III: The Metabolic Syndrome
Diagnosis is established when 3 of these risk
factors are present.
Risk Factor
Defining Level
Abdominal obesity
(Waist circumference†)
Men
Women
TG
HDL-C
Men
Women
>102 cm (>40 in)
>88 cm (>35 in)
150 mg/dL
<40 mg/dL
<50 mg/dL
Blood pressure
130/85 mm Hg
Fasting glucose
110 mg/dL
*Abdominal obesity is more highly correlated with metabolic risk factors than is BMI.
†Some men develop metabolic risk factors when circumference is only marginally
increased.
Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
New Features of ATP III
Focus on Multiple Risk Factors
• Diabetes: CHD risk equivalent
• Framingham projections of 10-year CHD risk
– Identify certain patients with multiple risk factors for
more intensive treatment
• Multiple metabolic risk factors (metabolic syndrome)
– Intensified therapeutic lifestyle changes
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New Features of ATP III
Modification of Lipid and Lipoprotein Classification
• LDL cholesterol <100 mg/dL—optimal
• HDL cholesterol <40 mg/dL
– Categorical risk factor
– Raised from <35 mg/dL
• Lower triglyceride classification cut points
– More attention to moderate elevations
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Hypertriglyceridemia and
Risk for CHD
• TG elevation is generally associated with
increased risk for CHD on univariate analysis
• Is the relation causal?
• Or is the TG elevation simply a marker for
CHD risk through its associations with such
conditions as type 2 diabetes mellitus, low
HDL-C, and obesity?
• The TG-CHD relation tends to weaken or
disappear on multivariate analysis
Hypertriglyceridemia and CHD Risk:
Associated Abnormalities
•Accumulation of chylomicron remnants
•Accumulation of VLDL remnants
•Generation of small, dense LDL-C
•Association with low HDL-C
•Increased coagulability
– plasminogen activator inhibitor (PAI-1)
– factor VIIc
–activation of prothrombin to thrombin
Association of Small, Dense LDL
With Insulin Resistance
Steady-state plasma glucose
12
n=19
10
Glucose
(mmol/L)
8
n=17
n=19
6
4
2
0
A
Intermediate
pattern
B
Adapted from Reaven GM et al. J Clin Invest. 1993;92:141-146.
Atherosclerosis in Diabetes
• Accelerated atherosclerosis is multifactorial and
begins years/decades prior to diagnosis of type 2
diabetes
• >50% of patients with newly diagnosed type 2
diabetes have CHD
• Risk for atherosclerotic events is 2- to 4-fold
greater in diabetics than in nondiabetics
• Atherosclerosis accounts for 65% of all diabetic
mortality
– 40% due to ischemic heart disease
– 15% due to other heart disease
– 10% due to cerebrovascular disease
Garber AJ. Clin Cornerstone. 2003;5:22-37.
Garber AJ. Med Clin North Am. 1998;82:931-948.
National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
Insulin Resistance and Atherosclerosis:
Posited Relationships
Insulin resistance
Hyperinsulinemia
Impaired
glucose
tolerance
Hypertriglyceridemia
Decreased HDL-C
Clinical diabetes
Accelerated atherosclerosis
Essential
hypertension
Interrelation Between Atherosclerosis
and Insulin Resistance
Insulin Resistance
Hypertension Obesity
HyperHypertriSmall,
Low HDL HypercoaguDiabetes
insulinemia
glyceridemia dense LDL
lability
Atherosclerosis
Progression to Atherosclerotic Clinical
Events in Patients With Diabetes
Hyperglycemia
Inflammation
Infection
Dyslipidemia
 AGE
 Oxidative
stress
 IL-6
 CRP
 SAA
 Defense
mechanisms
 Pathogen burden
Insulin Resistance
HTN
Endothelial
dysfunction
Subclinical Atherosclerosis
 LDL
 TG
 HDL
Thrombosis
 PAI-1
 TF
 tPA
Disease Progression
Atherosclerotic Clinical Events
AGE=advanced glycation end products; CRP=C-reactive protein; HDL=high-density
lipoprotein; HTN=hypertension; IL-6=interleukin-6; LDL=low-density lipoprotein;
PAI-1=plasminogen activator inhibitor-1; SAA=serum amyloid A protein;
TF=tissue factor; TG=triglycerides; tPA=tissue-type plasminogen activator
Biondi-Zoccai GGL et al. J Am Coll Cardiol. 2003;41:1071-1077.
New Recommendation for
Screening/Detection
• Complete lipoprotein profile preferred
– Fasting total cholesterol, LDL, HDL, triglycerides
• Secondary option
– Non-fasting total cholesterol and HDL
– Proceed to lipoprotein profile if TC 2.26 mmol/L or HDLc
<1.04 mmol/L
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LDL Cholesterol Goals and Cutpoints for Therapeutic
Lifestyle Changes (TLC) and Drug Therapy in
Different Risk Categories
Risk Category
CHD or CHD Risk
Equivalents
(10-year risk
>20%)
2+ Risk Factors
(10-year risk
20%)
0–1 Risk Factor
LDL Goal
(mmol/L)
<2.59
LDL Level at
Which to Initiate
Therapeutic
Lifestyle Changes
(TLC) (mmol/L)
LDL Level at
Which
to Consider
Drug Therapy
(mmol/L)
2.59
3.37
(2.59–3.34: drug
optional)
10-year risk 10–
20%: 3.37
<3.37
3.37
10-year risk <10%:
4.14
<4.14
4.14
4.9
(4.1–4.89: LDLlowering drug
optional)
L1-24
ADA: Glycemic Control, BP, and
Lipid Targets in Type 2 Diabetes
Glycemic control
Hemoglobin A1c
Preprandial plasma glucose
Peak postprandial plasma glucose
Blood pressure
Lipids
LDL-C
TG†
HDL-C
Goal
<7.0%*
90-130 mg/dL
<180 mg/dL
<130/80 mm Hg
<100 mg/dL
<150 mg/dL
>40 mg/dL‡
*Referenced to a nondiabetic range of 4.0%–6.0% using a DCCT-based assay.
†ATP III guidelines suggest when TG is 200 mg/dL, use non–HDL-C (TC minus
HDL-C); goal in patients with diabetes is 130 mg/dL (LDL-C goal + 30 mg/dL).
‡For women, an HDL-C goal 10 mg/dL higher may be appropriate.
DCCT = Diabetes Control and Complications Trial
ADA. Diabetes Care. 2003;26(suppl 1):S33-S50.
ADA: Treatment Decisions by LDL-C
Levels* in Adults With Type 2 Diabetes
Medical nutrition tx
Drug tx
Initiation
level
LDL-C
goal
Initiation
level
LDL-C
goal
With CHD, PVD,
or CVD
100
<100
100
<100
Without CHD,
PVD, and CVD
100
<100
130†
<100
Status
*Values represent mg/dL.
†Some authorities recommend initiation of drug therapy between 100 and
129 mg/dL.
CHD=coronary heart disease; PVD=peripheral vascular disease;
CVD=cardiovascular disease
ADA. Diabetes Care. 2003;26(suppl 1):S83-S86.
Benefits of cholesterol lowering
Meta-analysis of 38 primary and secondary intervention trials
Mortality log odds ratio
-0.0
-0.2
-0.4
-0.6
Total mortality (p=0.004)
CHD mortality (p=0.012)
-0.8
-1.0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
% in cholesterol reduction
Gould AL, et al. Circulation. 1998;97:94-952.
L1-27
Lipid Lowering Compounds
Agents
HMG-CoA
reductase
inhibitors (statins)
Bile acid
sequestrants
Nicotinic acid
Lipid Effects
LDL 
HDL 
TG 
LDL 
HDL 
TG no change or 
LDL 
HDL 
TG 
Plant stanols*
LDL 
(may be  in patients with
high TG)
HDL 
TG 
LDL 
Plant sterols*
LDL 
Fibric acids
Selected Side Effects
Myopathy,  liver
enzymes
Selected
Contraindications/Warnings
Active or chronic liver disease
Concomitant use of certain
drugs
Gastrointestinal distress, Dysbetalipoproteinemia, TG
constipation,  absorption >400 mg/dL
of other drugs
TG >200 mg/dL
Flushing; hyperglycemia,
hyperuricemia (or gout),
upper GI distress,
hepatotoxicity
Dyspepsia; gallstones,
myopathy, unexplained
non-CHD deaths in WHO
study
Chronic liver disease,
severe gout,
diabetes, hyperuricemia,
peptic ulcer disease
Severe renal, severe hepatic
disease
Not available
Not available
Not available
Not available
Adapted from NCEP ATP III. JAMA. 2001;285:2491; *Cater NB. Prev Cardiol. 2000;3:127.
L1-28
Landmark Clinical Trials
• Primary prevention
• Secondary prevention

WOSCOPS

4S

AFCAPS/TexCAPS

CARE
The Pyramid of Recent Trials
(Relative Size of the Various
Segments of the Population)
Very high cholesterol with
CHD or MI
4
S
Moderately high cholesterol in
high risk CHD or MI
LIPID
Normal cholesterol with
CHD or MI
CARE
WOSCOPS
High cholesterol
without CHD or MI
AFCAPS/TexCAPS
No history of CHD or MI
L1-29
West of Scotland Coronary
Prevention Study (WOSCOPS)
• Study design
– Primary prevention of
myocardial infarction
in 6595 men
– Mean baseline LDL: 4.97
mmol/L
• Study intervention
– Pravastatin 40 mg or placebo
• Primary endpoint
– Nonfatal MI and CHD death
Nonfatal MI & CHD death
12
Placebo (n=3293)
10
Pravastatin (n=3302)
31%
relative
risk
reduction
p < 0.001
8
Percent
with 6
event
4
2
0
1
2
3
4
5
6
Years
Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.
L1-30
AFCAPS/TexCAPS
•
Study design
– Primary prevention of
myocardial infarction in 6605
men and women with LDL
cholesterol levels 2.98 mmol/L
and TG <5.65 mmol/L
– Mean baseline LDL: 3.89
Fatal/nonfatal MI,
sudden cardiac death,
unstable angina
mmol/L
Study intervention
– Lovastatin 20-40 mg (to target
LDL of 2.85 mmol/L) or
placebo
•
Primary endpoint
– Composite of fatal or nonfatal
MI, sudden cardiac death,
unstable angina
Downs JR, et al. JAMA. 1998;279:1615-1622.
Placebo
Lovastatin
0.07
Cumulative incidence
•
0.06
37% risk
reduction
p<0.001
0.05
0.04
0.03
0.02
0.01
0.0
1
2
3
4
5
>5
Years of follow-up
L1-31
Scandinavian Simvastatin
Survival Study (4S)
• Study design
– Secondary prevention in 4444
patients with a history of angina
pectoris or acute MI
– Mean baseline LDL: 4.87 mmol/L
• Study intervention
• Primary endpoint
– Total mortality
1.00
Proportion alive
– Simvastatin 20-40 mg or
placebo
Total mortality
0.95
0.90
0.85
Simvastatin
Placebo
Log rank p=0.0003
0.80
0.00
0.0
1
2
3
4
5
This
improveme
nt in
survival is
accounted
for by the
42%
reduction in
coronary
events.
6
Years since randomization
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-
L1-32
Cholesterol and Recurrent Events Trial
(CARE)
• Study design
– Secondary prevention in 4159 men and
women with average cholesterol levels
– Mean baseline LDL: 3.6 mmol/L
Nonfatal MI or CHD death
• Study intervention
– Pravastatin 40 mg or placebo
– Nonfatal MI or CHD death
Incidence %
• Primary endpoints
Placebo
Pravastatin
15
Change in risk,
24% reduction
p=0.003
10
5
0
0.0
1
2
3
4
5
Years
Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.
L1-33
ADA 2005:Treatment recommendations
& goals for Dyslipidemia & Diabetes
• Patients with type 2 diabetes have an increased
prevalence of lipid abnormalities that contributes to
higher rates of CVD.
• Lifestyle modification focusing on the reduction of
saturated fat and cholesterol intake, weight loss (if
indicated),and increased physical activity has been shown
to improve the lipid profile in patients with diabetes.
• In individuals with diabetes over the age of 40 years with
a total cholesterol >=135 mg/dl, without overt CVD,
statin therapy to achieve an LDL reduction of 30-40%
regardless of baseline LDL levels is recommended. The
primary goal is an LDL<100 mg/dl (2.6 mmol/l).
ADA. Diabetes Care. 2005;Vol 28,Supplement 1,Jan 2005
ADA 2005:Treatment recommendations
& goals for Dyslipidemia & Diabetes
• For individuals with diabetes aged<40 years without overt
CVD, but at increased risk (due to other cardiovascular
risk factors or long duration of diabetes), who do not
achieve lipid goals with lifestyle modifications alone, the
addition of pharmacological therapy is appropriate and
the primary goal is an LDL cholesterol <100 mg/dl (2.6
mmol/l).
• People with diabetes and overt CVD are at very high risk
for further events and should be treated with a statin.
• A lower LDL cholesterol goal of < 70 mg/dl (1.8 mmol/l),
using a high dose of a statin, is an option in these high
risk patients with diabetes and overt CVD.
ADA. Diabetes Care. 2005;Vol 28,Supplement 1,Jan 2005
ADA 2005:Treatment recommendations
& goals for Dyslipidemia & Diabetes
• Lower triglycerides to<150 mg/dl (1.7mmol/l) and raise
HDL cholesterol to> 40 mg/dl (1.15 mmol/l). In
women,an HDL goal 10 mg/dl higher (>50 mg/dl) should
be considered.
• Lowering triglycerides and increasing HDL cholesterol
with a fibrate is associated with a reduction in
cardiovascular events in patients with clinical CVD,low
HDL, and near-normal levels of LDL.
• Statin therapy is contraindicated in pregnancy.
ADA. Diabetes Care. 2005;Vol 28,Supplement 1,Jan 2005
ABCs of CVD Risk Management
Intervention
A • Antiplatelets/anticoagulants
• ACE inhibitors/ARBs
• Antianginals
B • BP control
• ß-blockers
Goals
• Treat all high-risk patients
with one of these
• Optimize BP especially if
CVD, type 2 diabetes, or
low EF present
• Relieve anginal symptoms,
allow patient to exercise
• Aim for BP <130/85 mm Hg,
or <130/80 mm Hg for type
2 diabetes
• Post MI or low EF
CVD=cardiovascular disease; ACE=angiotensin converting enzyme;
ARB=angiotensin receptor blocker; BP=blood pressure; EF=ejection fraction;
MI=myocardial infarction.
Braunstein JB et al. Cardiol Rev. 2001;9:96-105.
ABCs of CVD Risk Management (Cont.)
Intervention
C • Cholesterol Management
Goals
• LDL-C targets,ATP III
guidelines
-CHD,CHD risk
equivalents:<100 mg/dL
->2 RF<130 mg/dL
-0-1 RF:<160 mg/dL
• HDL-C:>40 mg/dL (men)
• Cigarette smoking cessation
•
>50 mg/dL (women)
• TG:<150 mg/dL
• Long term smoking cessation
1. Braunstein JB et al. Cardiol Rev. 2001;9:96-105.
2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA.
2001;285:2486-2497.
ABCs of CVD
Risk Management (cont.)
Intervention
D
• Dietary/weight counseling
• Diabetes management
E
• Exercise
• Education of patients and
families
Goals
• Achieve optimal BMI
•  saturated fats;  fruits, vegetables,
fiber
• Achieve HbA1c <7%
• Improve physical fitness
(aim for 30 min/d on most days per
week)
• Optimize awareness of CAD risk
factors
BMI=body mass index; HbA1c=glycosylated hemoglobin;
CAD=coronary artery disease.
Braunstein JB et al. Cardiol Rev. 2001;9:96-105.