Cardiovascular Disease: The Leading Cause of Death in US Women in 1995

1
Cardiovascular Disease The Leading Cause of
Death in US Women in 1995
Heart disease
375
Cerebrovascular disease
96.4
Lung cancer
60.6
COPD
48.9
Pneumonia/Influenza
45.1
Breast cancer
43.8
Accidents
31.9
Diabetes
33.1
Ovarian cancer
9.9
0
50
100
150
200
250
300
350
400
Deaths (1,000)
COPDchronic obstructive pulmonary
disease. Adapted from Anderson RN et al. Monthly
Vital Statistics Report.Vol 45(suppl 2)June 12,
1997.
2
PDAY Prevalence of Lesions in LAD
Age (y) Prevalence ()
100
15-19
Women
80
25-29
Men
60
60
40
40
20
20
0
0
60
30-34
20-24
60
40
40
20
20
0
0
0
1
2
3
4
5
0
1
2
3
4
5
AHA lesion grade
AHA lesion grade
Error barSE.
McGill HC Jr, et al. Circulation.
2000102374-379.
3
Relationship Between Cholesterol and CHD Risk
Epidemiologic Trials
Framingham Study (n5209)

• (MRFIT) (n361,662)

50 40 30 20 10
Castelli WP. Am J Med. 1984,764-12 Gotto AM Jr,
et al. Circulation. 1990,811721-1733
4
Meta-Analysis of Statin Trials
HDL-C
5
Fatal CHD
Coronary Events
Total Mortality
TG
LDL-C
0
5
-5
-10
-13
Change ()
-15
-20
-21
-25
-28
-30
-29
-31
-35
LaRosa JC et al. JAMA. 19992822340-2346.
5
Beyond Cholesterol Predicting Cardiovascular
Risk In the 21st Century
Cardiovascular Risk
6
Standard Lipid Profile

• 49 year old female with type 2 diabetes and
  documented CAD.
• Total Cholesterol 376 mg/dl
• HDL 38 mg/dl
• Triglycerides 576 mg/dl
• LDL ?

7
Comprehensive Lipoprotein Profile

• LDL 204 mg/dl.
• Dense pattern B LDL.
• Elevated Lp(a).
• Low HDL2 .
• Elevated remnant triglyceride-rich lipoproteins.

8
LIPOPROTEIN CLASSES
Nascent HDL
9
Methods for Comprehensive Lipoprotein Analysis

• Gradient gel electrophoresis (GGE).
• Nuclear magnetic resonance (NMR).
• Vertical autoprofile (VAP).

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VAP Profile of the 49 year old female with type 2
diabetes and documented CAD
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Characteristics of LDL Phenotype B

• Common heritable trait
• frequency 2530 of population
• Autosomal dominant inheritance
• Reduced penetrance in males ?20 yr and in
  premenopausal females
• Associated with
• increased TG, VLDL, and IDL and reduced HDL2
• threefold increase in MI risk

14
LDL pattern B

• Insulin resistance. Dense LDL is an integral
  feature of the insulin resistance syndrome.
• Type 2 diabetes. Dense LDL predicts future type 2
  diabetes.

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Lp(a)

• When elevated Lp(a) is associated with the
  atherogenic lipoprotein profile (low HDL2,
  elevated dense LDL, IDL, dense VLDL and VLDL),
  the increased risk is 25.  
• If two or more non-lipid risk factors are also
  present (hypertension, diabetes, cigarette
  smoking, or high total homocysteine) the
  increased risk is 122.

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HDL2

• Inheritance. HDL2 is highly inherited but HDL3 is
  not.
• Gender. HDL2 is higher in women than in men and
  accounts for perhaps 50 of womens increased
  longevity.

19
HDL2

• Type 2 diabetes. A low level of HDL2 is
  associated independently with type 2 diabetes.
• Smoking. Both active and passive cigarette
  smoking decrease HDL2.

20
HATSQuestion

• In Patients with CAD and Low HDL-C
• Does Niacin Plus Simvastatin Improve on statin
  expectations?

Brown BG, et al, NEJM, 2451583 (2001).
21
HATS Lipid Results
Simvastatin Niacin
B. Greg Brown As presented at the 2000 AHA
Abstract 2461
22
HATS Primary Clinical Endpoint
CAD death, Non-fatal MI, CVA or Revascularization
100
97
SN-P
90
Free of Event
90 reduction
PP-P
80
Relative Risk 0.102 P 0.031
76
70
0
3
2
1
Years
B. Greg Brown As presented at the 2000 AHA
Abstract 2461
23
MULTIVARIANT RR OF MI ADH3 GENOTYPE AND ALCOHOL
CONSUMPTION
rr 0.14
Hines, et. al., NEJM, 344549, 2001
24
HDL LEVELS ADH3 GENOTYPE AND ALCOHOL CONSUMPTION
16
33
Hines, et. al., NEJM, 344549, 2001
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IDL

• Insulin resistance. Hyperinsulinemia and insulin
  resistance are associated with elevated levels of
  IDL.
• Type 2 diabetes. Non-insulin dependent diabetes
  is associated with elevated IDL.
• Life style. Since IDL is under strong genetic
  control, diet and exercise lower IDL only
  modestly.

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VLDL3

• Insulin resistance. Hyperinsulinemia and insulin
  resistance are associated with elevated levels of
  VLDL3.
• Type 2 diabetes. Non-insulin dependent diabetes
  is associated with elevated VLDL3.

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Evolution of Statins
1st Generation
(fermentation)
Simvastatin
Pravastatin
Lovastatin
3rd Generation
2nd Generation
(synthetic
(synthetic-active
racemate)
enantiomer)
Fluvastatin
Cerivastatin
Atorvastatin
30
Combination Nicotinic Acid-Statin Therapy
31
UAB CLINICAL EXPERIENCE
COMBINATION THERAPY WITH NICOTINIC ACID AND
STATINS
NCEP
LDL
LDL
n 22
NA
S
TC
HDL
HDL
Lp(a)
LDL-R
IDL
VLDL
VLDL
VAP TG
HDL
2
3
3
LDL
B
A
Baseline
0.0
0.0
243.0
33.6
28.1
5.5
8.2
117.5
22.6
148.3
71.5
46.0
61.0
19.2
309.9
Rx
3.1
13.0
152.2
48.2
35.4
12.8
8.3
71.8
9.5
89.5
15.5
56.2
14.5
5.8
75.5
Change
-37
43
26
133
1
-39
-58
-40
-78
22
-76
-70
-76
p

lt 0.05
0.000
0.000
0.000
0.001
0.959
0.000
0.000
0.000
0.000
0.274
0.000
0.000
0.000
Segrest, et. al., As presented at the 1999 AHA
Abstract 1339
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Risk Similar in Patients With Type 2 Diabetes and
No Prior MI vs Nondiabetic Subjects With Prior MI
100
80
60
Survival()
40
Nondiabetic subjects without prior MI
(n1,304)Diabetic subjects without prior MI
(n890)Nondiabetic subjects with prior MI
(n69)Diabetic subjects with prior MI (n169)
20
0
0
1
2
3
4
5
6
7
8
Year
Haffner SM et al. N Engl J Med. 1998339229-234.
33
NHANES III More type II Diabetes
Diabetes
38 ?
Impaired Fasting Glucose
15
49 ?
12.3
10
9.7
Population ()
8.9
6.5
5
0
19761980
1988 1994
1988 1994
1976 1980
Harris MI et al. Diabetes Care. 199821518-524.
34
Natural History of Type 2 Diabetes
Obesity IFG Diabetes
Uncontrolled hyperglycemia
350
Post-meal Glucose
300
250
Fasting Glucose
Glucose (mg/dL)
200
150
100
50
250
Insulin Resistance
200
Relative Function ()
150
100
Insulin Level
50
Beta-cell failure
0
-10
-5
0
5
10
15
20
25
30
Years of Diabetes
IFG impaired fasting glucose
Adapted from International Diabetes Center
(IDC) Minneapolis, Minnesota
35
Insulin Resistance Syndrome
36
Rosiglitazone vs Glyburide Mean FPG
260 240 220 200 180 160 140
FPG (mg/dL)
Glyburide
RSG 8 mg/day
0
2
4
6
8
12
16
28
40
52
Treatment Week
Observed Case Population (OCP) Mean SE Given
as 4 mg BID
Study 080
37
Estimated survival among patients with CAD,
according to plasma total homocysteine levels
Nygard, et al, NEJM, 337230 (1997)
38
Homocysteine Role in Atherogenesis

• Linked to pathophysiology of arteriosclerosis in
  1969
• CVD patients have elevated levels of plasma
  homocysteine
• May cause vascular damage to intimal cells
• Elevated levels linked to
• genetic defects
• exposure to toxins
• diet
• Increased dietary intake of folate and vitamin B6
  may reduce CVD morbidity and mortality

McCully KS. Am J Pathol. 196956111-128. McCully
KS. JAMA. 1998279392-393. Rimm EB et al. JAMA.
1998279359-364.
39
ATP III New Features of GuidelinesFocus on
Multiple Risk Factors

• Persons with diabetes without CHD raised to level
  of CHD risk equivalent
• Framingham 10-year absolute CHD risk projections
  used to identify certain patients with ?2 risk
  factors for more intensive treatment
• Persons with multiple metabolic risk factors (the
  metabolic syndrome) identified as candidates for
  intensified therapeutic lifestyle changes (TLC)

Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
40
ATP III New Features of GuidelinesUpdated
Lipid/Lipoprotein Classifications

• Optimal LDL-C level identified as lt100 mg/dL
• Categorical low HDL-C raised to lt40 mg/dL to
  moreaccurately define patients at increased risk
• TG classification cutpoints lowered to focus
  moreattention on moderate elevations
• normal lt150 mg/dL
• borderline high 150199 mg/dL
• high 200499 mg/dL
• very high ?500 mg/dL

Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
41
ATP III LDL-C, HDL-C, TC Classification
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
42
ATP III Major CHD Risk FactorsOther Than LDL-C

• Cigarette smoking
• Hypertension BP ?140/90 mm Hg or on
  antihypertensive medication
• Low HDL-C ?40 mg/dL
• Family history of premature CHD (1st-degree
  relative)
• male relative age ?55 years
• female relative age ?65 years
• Age
• male ?45 years
• female ?55 years

HDL-C ?60 mg/dL is a negative risk factorand
negates one other risk factor.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
43
ATP III Management of Elevated TG
Primary aim of therapy is to get to LDL-C
goal. Primary aim of therapy is to reduce risk
for pancreatitis through TG lowering first, then
focus on LDL-C. To achieve nonHDL-C goal (set
at 30 mg/dL higher than LDL-C goal), intensify
therapy with LDL-Clowering drug, or add
nicotinic acid or fibrate.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
44
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 increased.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
45
ATP III Management of Diabetic Dyslipidemia

• Primary target of therapy identification of
  LDL-C goal for persons with diabetes lt100 mg/dL
  
• Therapeutic options
• LDL-C 100129 mg/dL increase intensity of TLC
  add drug to modify atherogenic dyslipidemia
  (fibrate or nicotinic acid) intensify risk
  factor control
• LDL-C ?130 mg/dL simultaneously initiate TLC and
  LDL-Clowering drugs
• TG ?200 mg/dL nonHDL-C becomes secondary target

Note Diabetic dyslipidemia is essentially
atherogenic dyslipidemia in persons with type 2
diabetes.NonHDL-C goal is set at 30 mg/dL
higher than LDL-C goal.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
46
ATP III LDL-C Measurements in Patients
Hospitalized for Major Coronary Events

• Measure LDL-C on admission or within 24 hours
• General recommendations at discharge
• LDL-C ?130 mg/dL discharge on drug therapy
• LDL-C 100129 mg/dL use clinical judgment
• Advantages of initiating drug therapy at
  discharge
• motivates patients to begin/continue
  risk-lowering therapy
• emphasizes consistency and continuous follow-up
  no treatment gap
• may reduce early clinical events

Some authorities recommend initiating lower-dose
drug therapy when LDL-C gt100 mg/dL in patients
with CHD-related illness.
Expert Panel on Detection, Evaluation, and
Treatment ofHigh Blood Cholesterol in Adults.
JAMA. 20012852486-2497.
47
Case Study 2 Standard Lipid Profile

• 56-year-old female
• TC 450 mg/dL
• On oral HRT

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Case Study 2

• What is her risk for CAD?
• How do you treat her?

49
Case Study 2

• TG 4300 mg/dL
• Past history of acute pancreatitis
• Family history of premature CAD

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Causes of Hypertriglyceridemia

• Primary
• Genetic defect in triglyceride metabolism
• Secondary
• Diet high in cholesterol and saturated fat
• Disorders
• Diabetes mellitus
• Obesity
• Alcohol consumption
• Renal failure
• Systemic lupus erythematosus
• Lipodystrophy
• Glycogen storage disease

• Drugs
• Oral estrogens, contraceptives, tamoxifen
• Glucocorticoids
• Retinoic acid derivatives
• HIV protease inhibitors
• Rapamycin
• Bile-acid binding resins
• Beta blockers
• Thiazide diuretics