Download - Pfizer Talk Final
Pfizer Talk
Family Medicine
13/1/2010Dr Ihab Suliman
43 years old male with Chest Pain
Acute Inferior STEMI in NSR.
Atherosclerosis
The Impact of Elevated LDL-C and
Associated Atherosclerosis
Atherosclerosis is caused by a build-up of plaque in
arterial walls, obstructing blood flow
Atherosclerosis accounts for more than 70%
of all deaths from cardiovascular disease in the US
Elevated LDL (low-density lipoprotein) cholesterol
increases risk of atherosclerosis and coronary heart
disease
The risk of coronary heart disease increases by about
2% for each 1% elevation in total cholesterol
National Center for Health Statistics. Health, United States, 2005.http://www.cdc.gov/nchs/hus.htm. Accessed May 17, 2006
Kwiterovich PO Jr. Am J Cardiol. 1998,82:3U-17U
Cholesterol is important in so many metabolic
activities , there fore it is more important in
adults or infants????
What is the normal Cholesterol level in
Infancy???.
Cholesterol Levels By Species
Mean Total Cholesterol Level
50 70 90 110 130 150 170 190 210
Wild Primates:
Hunter-Gatherer
Humans: Hazda
InuitIKungPygmy
San
BaboonHowler Monkey
Night Monkey
Wild Mammals:HorseBoar
PeccaryBlack RhinocerosAfrican Elephant
Modern Human:
Infant
Adult American
JACC 2004;43:2142-6
Discovery of statins Some drugs available but not effective
In 1971,Endo and Kuroda (Sankyo Pharmaceuticals in Japan) began search for better drugs
Cholesterol pathway known and they wanted to find a HMG-CoA reductase inhibitor – looked for a microorganism – screened over 6000 Two (3rd later) cmpds identified - one was from Penicillium
citrinum - named mevastatin
In 1976 isolated and crystallized
Clinical trials started in 1978 and quickly stopped because of animal tumors
Modifiable Risk Factors
Medical conditions
Hypertension
Diabetes mellitus
Hypercholesterolemia
Obesity
Insulin resistance?
Cardiac diseases
Atrial fibrillation
Coronary artery disease
CHF
Behaviours
Cigarette smoking
Heavy alcohol use
Physical inactivity
Causes of death, 2001:
1. Infectious and parasitic diseases: 14.9 million
2. Heart diseases: 11.1 million
3. Cancers: 7.3 million
4. Stroke: 5.5 million
5. Respiratory diseases: 3.6 million
6. Accidents, fires, drowning, etc.: 3.5 million
7. Maternal and perinatal: 3.0 million
8. Violence (war, homicide, suicide): 1.6 million
World Health Organization
World Health Report 2002
Population: 6,122,210,000
Deaths: 56,554,000
USA
6.
1.
2.
3.
4.
5.
Therapeutic lifestyle change is the cornerstone of the
management of hyperlipidemia and dyslipidemia?
LDL-C with AHA diet: ~ 5%
Response variability: familial/genetic
Hypocaloric diets in overweight & obese
A high fat, low carb diet does not worsen serum
lipids/lipoproteins and improves glycemic control in
patients with diabetes
LDL-C is unchanged
HDL-C is unchanged or slightly higher
Triglyceride is lower by~25%
Variability in response?
HbA1c better than with LFHC diet
Dietary Nuances
Fish: twice/wk; omega-3 fatty acids, 1000 mg/d
Eliminate/reduce trans FA
Plant stanols/sterols reduce LDL-C by ~10%
Antioxidant vitamins are not cardioprotective and interfere with effects of niacin on HDL-C
Homocysteine: folic acid, vitamins B6 and B12
not proven to be cardioprotective.
The 2004 NCEP LDL-C goal:
lower may be better
Acute Coronary Syndromes
• MIRACL: LDL-C, 125 72 mg/dl
• PROVE-IT: LDL-C, 106 62 mg/dl
Stable CHD
• HPS: benefit if basal LDL-C < 100 mg/dl
• ALLIANCE: 111 95 mg/dl
• REVERSAL: 150 79 mg/dl
How low a LDL-C is safe?
Newborn LDL-C is 35-50 mg/dl.
Patients with hypobetalipoproteinemia are healthy
and have enhanced survival
ATP III Treatment Priorities
Reduce LDL-C to goal (new goals)
Correct residual lipid/lipoprotein abnormalities(
non-HDL-cholesterol)
Address the metabolic syndrome
Utility of the non-HDL-cholesterol
Total minus HDL-C
Includes all atherogenic lipoproteins
• LDL-C, Lp(a), IDL, VLDL
Surrogate for apoprotein B
Optimum; add 30 mg/dl to LDL-C goals
All patients should receive TLC advise.
Simultaneous drug therapy should be started
in:
Patients with symptomatic CHD
All high risk patients
Intermediate risk
• men@40-45 yrs
• women@50-55 yrs
Options for reducing LDL-
cholesterol
• Statins
• Cholesterol absorption inhibitors
• Bile acid binding resins
• Niacin
Muscle Adverse Effects
Myalgia
Weakness
Fatigue
Myopathy without CK
Predisposing factors:• Combined hyperlipidemia
• Subclinical hypothyroidism
• Suboptimum thyroxine replacement
MODIFY RISK FACTORS
Hyperlipidemia in Pregnancy TC & TG levels increase throughout pregnancy
average cholesterol increase: 30 to 40 mg/dL around weeks
36 to 39
TGs may increase as much as 150 mg/dL
Drug therapy typically not initiated/continued during
pregnancy
TLC is the mainstay but BARs & absorption inhibitors
may be considered in high risk patients
ezetimibe: category C
Statins: category X
24
Statin Therapy Can Reduce the
Risk of Coronary Heart Disease (CHD)
Friday KE. Exp Biol Med. 2003,228:769-778
Wilt TJ et al. Arch Intern Med. 2004;164:1427-1436
Key Clinical Trial Data Efficacy Endpoint
Primary prevention
WOSCOPS
(pravastatin 40 mg)31% relative-risk (r-risk) reduction inCHD death or myocardial infarction
AFCAPS/TexCAPS
(lovastatin 20-40 mg)37% r-risk reduction in 1st acute coronary event
Secondary Prevention
4S
(simvastatin 10-40 mg)30% r-risk reduction in all-cause mortality
CARE
(pravastatin 40 mg)24% r-risk reduction in CHD death or MI
LIPID
(pravastatin 40 mg)24% r-risk reduction in CHD mortality
TJ Wilt meta-analysis 23% decreased CHD mortality
Diabetic Dyslipidemia Characterized by hypertriglyceridemia, low HDL, &
minimally elevated LDL
DM ATP III CHD risk equivalent
Small, dense LDL (pattern B) in DM patients is more
atherogenic than larger, more buoyant LDL (pattern A)
1˚target: LDL
Goal of treatment: LDL-C < 100 mg/dL
LDL > 130 mg/dL: TLC + drug therapy often required
Statins often considered initial drugs of choice
26
Expert Panel on Detection E, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
Diabetic Dyslipidemia
Collaborative Atorvastatin Diabetes Study (CARDS)
LDL lowering for 1˚ CHD prevention in type 2 DM
Randomized, double-blinded placebo controlled
Atorvastatin 10 mg/day versus placebo (n=2,838)
diabetes to reduce first CHD events
Baseline LDL: 118 mg/dL; LDL ↓ 46 mg/dL with
atorvastatin
27
Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2
diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial.
Lancet 2004;364:685–696.
Collaborative Atorvastatin Diabetes Study (CARDS)
Type 2 diabetes mellitus
Men and women 40–75 years
of age
Primary CHD and stroke
prevention
LDL-C 160 mg/dL ( 4.14
mmol/L)
TG 600 mg/dL
( 6.78 mmol/L)
1 additional RF
HTN (or on HTN
treatment)
Retinopathy
Albuminuria
Current smoking
Colhoun HM et al. Lancet 2004;364:685-696.
Patient Population
Primary endpoint: time to first major CV
event (CHD death, nonfatal MI, unstable
angina, resuscitated cardiac arrest, coronary
revascularization, stroke
Secondary endpoints: total mortality, any CV
endpoint, lipids, and lipoproteins
2838 patients
4-year follow-up
Atorvastatin 10 mg (n=1428)
Double-blind placebo (n=1410)
CARDS: Patient Baseline
CharacteristicsPlacebo
(n = 1410)
Atorvastatin
(n = 1428)
Age
Mean (SD) years 61.8 (8.0) 61.5 (8.3)
<60 529 (38%) 558 (39%)
60–70 708 (50%) 703 (49%)
>70 173 (12%) 167 (12%)
Women 453 (32%) 456 (32%)
White ethnicity 1326 (94%) 1350 (95%)
BMI
Mean (SD), kg/m2 28.8 (3.5) 28.7 (3.6)
Obese (BMI >30 kg/m2) 538 (38%) 515 (36%)
Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.
CARDS: Patient Baseline LipidsPlacebo
(n = 1410)
Mean (SD)
Atorvastatin
(n = 1428)
Mean (SD)
Total cholesterol (mg/dL)
(mmol/L)
207 (32)
5.35 (0.82)
207 (32)
5.36 (0.83)
LDL cholesterol (mg/dL)
(mmol/L)
117 (27)
3.02 (0.70)
118 (28)
3.04 (0.72)
HDL cholesterol (mg/dL)
(mmol/L)
55 (13)
1.42 (0.34)
54 (12)
1.39 (0.32)
Triglycerides* (mg/dL)
(mmol/L)
148 (104–212)
1.67 (1.17–2.40)
150 (106–212)
1.70 (1.20–2.40)
*Median (interquartile range)
Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.
0
80
160
240
CARDS: Lipid Levels by Treatment
Total Cholesterol (mg/dL)
Average difference 26%,
54 mg/dL; P<0.0001
Media
n T
C (
mg/d
L)*
Years of Study
0 1 2 3 4 4.50
40
80
120
160
Media
n L
DL-
C (
mg/d
L)*
Years of Study
0 1 2 3 4 4.5
LDL Cholesterol (mg/dL)
Average difference 40%,
46 mg/dL; P<0.0001
Atorvastatin
Atorvastatin
PlaceboPlacebo
Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.
0
5
10
15
CARDS: Effect of Atorvastatin on the Primary
Endpoint: Major CV Events Including StrokeCum
ula
tive H
azard
, (%
)
Years0 1 2 3 4
Relative Risk Reduction 37% (95% CI, 17–52)P = 0.001
1410
1428
1351
1392
Placebo
Atorvastatin
4.75
1306
1361
1022
1074
651
694
305
328
Placebo127 events
Atorvastatin83 events
Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.
CARDS: Adverse and Serious Adverse
Events
Type of Event
Patients (%) with Event
Placebo
(n = 1410)
Atorvastatin 10 mg
(n = 1428)
Serious adverse event
possibly associated with
study drug
20 (1.1%) 19 (1.1%)
Discontinued for AE 145 (10%) 122 (9%)
Rhabdomyolysis 0 0
Myopathy AE report 1 (0.1%) 1 (0.1%)
CPK 10 ULN 10 (0.7%) 2 (0.1%)
ALT 3 ULN 14 (1%) 17 (1%)
AST 3 ULN 4 (0.3%) 6 (0.4%)
Colhoun HM et al. Lancet 2004;364:685-696.
Diabetic Dyslipidemia
CARDS trial: 37% reduction in composite 1˚end
point
1˚ endpoint: acute CHD death, nonfatal MI,
hospitalized unstable angina, resuscitated cardiac
arrest, coronary revascularization, or stroke
Suggests diabetics should have target LDL much
lower than 100 mg/dL
34
Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2
diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial.
Lancet 2004;364:685–696.
ASCOT: Primary Endpoint:
Nonfatal MI/Fatal CHD
0
1
2
3
4
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Cu
mu
lati
ve I
ncid
en
ce (
%)
36%
reduction
HR = 0.64 (0.50-0.83)
Atorvastatin 10 mg Number of events 100
Placebo Number of events 154
P = 0.0005
Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.
Comparing 2 statin drugs
Atarvastatin – 80 mg.
Pravastatin – 40 mg.
Equivalent doses
Trial was designed to demonstrate non-inferiority of pravastatin. Instead, it showed ataravastatin to be superior.
Not only did ataravastatin lower cholesterol more (and faster), but it lowered death rate by 16%
Study was stopped “early.”
FDA 2007
The FDA approved atorvastatin for reducing
the risk for nonfatal MI, reducing the risk for
fatal and nonfatal strokes, for use in certain
types of heart surgery, for reductions in the risk
of hospitalization for heart failure, and to reduce
chest pain in patients with heart disease.
Atorvastatin is the first cholesterol-lowering
drug to be approved for reducing the risk of
hospitalization for heart failure.
Thank You
Very Much