Cholesterol, Cholesterol Therapies, and Cholesterol Guidelines

1

• Cholesterol, Cholesterol Therapies, and
  Cholesterol Guidelines
• Andrew P. DeFilippis, Ty J. Gluckman, James Mudd,
  Catherine Campbell, Vera Bittner, Gregg Fonarow
  Roger S. Blumenthal

2
Lipoprotein Classes
HDL
LDL
Chylomicrons,VLDL, and their catabolic remnants
gt 30 nm
2022 nm
915 nm
Potentially pro-inflammatory
Potentially anti-inflammatory
Doi H et al. Circulation 2000102670-676 Colome
C et al. Atherosclerosis 2000149295-302
Cockerill GW et al. Arterioscler Thromb Vasc
Biol 1995151987-1994
3
The Role of Lipoproteins in Atherogenesis
Endothelialinjury
High plasmaLDL
HDL
Adherenceof platelets
LDLVLDL
LDL infiltrationinto intima
LCATAPO-A1
Releaseof PDGF
Oxidativemodificationof LDL
Liver
Othergrowthfactors
Macrophages Foam cells Fatty streak
Cholesterolexcreted
Advancedfibrocalcificlesion
APO-A1Apolipoprotein A1, HDLHigh density
lipoprotein, LCATLecithin cholesterol
acyltransferase, LDLLow density lipoprotein,
PDGFPlatelet-derived growth factor, VLDLVery
low density lipoprotein
4
CHD Risk According to LDL-C Level
3.7 2.9 2.2 1.7 1.3 1.0
Relative Risk for Coronary Heart Disease (Log
Scale)
40 70 100 130 160 190
LDL-Cholesterol (mg/dL)
CHDCoronary heart disease, LDL-CLow-density
lipoprotein cholesterol
Grundy S et al. Circulation 2004110227-39
5
Therapies to Lower LDL-C
Drug(s)
Class
Atorvastatin (Lipitor) Fluvastatin (Lescol
XL) Lovastatin (generic and Mevacor) Pravastatin
(Pravachol) Rosuvastatin (Crestor) Simvastatin
(Zocor)
3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA)
reductase inhibitors Statins
Cholestyramine (generic and Questran) Colesevelam
(Welchol) Colestipol (Colestid)
Bile acid sequestrants
Ezetimibe (Zetia)
Cholesterol absorption inhibitor
Nicotinic acid
Niacin
Soluble fiber Soy protein Stanol esters
Dietary Adjuncts
6
HMG-CoA Reductase Inhibitor Mechanism of Action
Inhibition of the Cholesterol Biosynthetic Pathway
Squalene synthase
Dolichol
HMG-CoA Reductase
Acetyl CoA
HMG- CoA
Farnesyl pyrophosphate
Mevalonate
Squalene
Cholesterol
Farnesyl- transferase
E,E,E-Geranylgeranyl pyrophosphate
Farnesylated proteins
Geranylgeranylated proteins
Ubiquinones
7
HMG-CoA Reductase Inhibitor Mechanism of Action
VLDL
Cholesterol synthesis
Apo B
LDL receptor (BE receptor) synthesis
LDL-Rmediated hepatic uptake of LDL and VLDL
remnants
Apo E
Serum LDL-C
Intracellular Cholesterol
Apo B
Serum VLDL remnants
Serum IDL
Systemic Circulation
Hepatocyte
The reduction in hepatic cholesterol synthesis
lowers intracellular cholesterol, which
stimulates upregulation of the LDL receptor and
increases uptake of non-HDL particles from the
systemic circulation
8
HMG-CoA Reductase Inhibitor Dose-Dependent Effect
The Rule of 6s
Each doubling of the statin dose produces an
additional 6 (approximate) reduction in the
LDL-C level
Illingworth DR. Med Clin North Am 20008423-42
9
HMG-CoA Reductase Inhibitor Reduction in LDL-C
A Meta-analysis of 164 Trials
Data presented as absolute reductions in LDL-C
(mg/dL) and percent reductions in LDL-C (in
parentheses) Standardized to LDL-C 186 mg/dL
(mean concentration in trials) before Rx.
Independent of pre-Rx LDL-C Maximum dose of 80
mg/d administered as two 40-mg tablets Not FDA
approved at 80 mg/d
FDAFood and Drug Administration, LDL-CLow
density lipoprotein cholesterol, RxTreatment
Law MR et al. BMJ 20033261423-1427
10
HMG-CoA Reductase Inhibitor Trials Chronology
Study Population Primary prevention Acute
coronary syndromes Chronic Coronary heart disease
11
HMG-CoA Reductase Inhibitor Primary Prevention
West of Scotland Coronary Prevention Study
(WOSCOPS)
6,595 men with moderate hypercholesterolemia
randomized to pravastatin (40 mg) or placebo for
5 years Statins provide significant
benefit in those with average cholesterol levels
31 RRR
9
7.5
6
5.3
Rate of MI or CHD death ()
3
Plt0.001
0
Placebo
Pravastatin
CHDCoronary heart disease, MIMyocardial
infarction, RRRRelative risk reduction
Shepherd J et al. NEJM 19953331301-1307
12
HMG-CoA Reductase Inhibitor Primary Prevention
Air Force/Texas Coronary Atherosclerosis
Prevention Study (AFCAPS/TEXCAPS)
6,605 patients with average LDL-C levels
randomized to lovastatin (20-40 mg) or placebo
for 5 years Statins provide benefit in
those with average LDL-C levels
37 RRR
5.5
6
4
3.5
Rate of MI, unstable angina, or SCD ()
2
Plt0.001
0
Placebo
Lovastatin
MIMyocardial infarction, RRRRelative risk
reduction, SCDSudden cardiac death
Downs JR et al. JAMA 199827916151622
13
HMG-CoA Reductase Inhibitor Primary Prevention
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack TrialLipid Lowering Arm
(ALLHAT-LLA)
10,355 patients with HTN and gt1 CHD risk factor
randomized to pravastatin (40 mg) or usual care
for 5 years There is no significant
difference between the two treatment arms, but a
high rate of cross-over
18
Pravastatin Usual care
15
12
32 cross-over among patients with CHD
Cumulative rate
9
6
3
0
Years
CHDCoronary heart disease, HTNHypertension,
RRRelative risk
ALLHAT Collaborative Research Group. JAMA
20022882998-3007
14
HMG-CoA Reductase Inhibitor Primary Prevention
Anglo-Scandinavian Cardiac Outcomes TrialLipid
Lowering Arm (ASCOT-LLA)
10,305 patients with HTN randomized to
atorvastatin (10 mg) or placebo for 5
years Statins provide significant
benefit in moderate- to high-risk individuals by
lowering LDL-C levels below current goals
4
Atorvastatin 90 mg/dl Placebo 126 mg/dl
3
36 RRR
2
Cumulative incidence of MI and fatal CHD ()
1
P0.0005
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Follow-up (yr)
CHDCoronary heart disease, RRRelative risk
Post-treatment LDL-C level
Sever PS et al. Lancet. 20033611149-1158
15
HMG-CoA Reductase Inhibitor Primary Prevention
Relationship between LDL-C Levels and Event Rates
in Primary Prevention Statin Trials
10
Statin
8
Placebo
WOSCOPS
WOSCOPS
6
AFCAPS
AFCAPS
CHD event rate ()
4
ASCOT
2
ASCOT
0
P0.0019
1
195
175
155
135
115
95
75
55
LDL cholesterol (mg/dL)
AFCAPS Air Force/Texas Coronary Atherosclerosis
Prevention Study, ASCOT Anglo-Scandinavian
Cardiac Outcomes TrialLipid Lowering Arm,
WOSCOPS West of Scotland Coronary Prevention
Study
OKeefe JH Jr et al. JACC 2004432142-6
16
HMG-CoA Reductase Inhibitor Secondary Prevention
Myocardial Ischemia Reduction with Aggressive
Cholesterol Lowering (MIRACL) Trial
3,086 pts with an ACS randomized to atorvastatin
(80 mg) or placebo for 16 weeks Acute
intensive treatment significantly reduces event
rates
17.4
Atorvastatin Placebo
14.8
Combined cardiovascular event rate ()
RR0.84, P0.048
4
8
12
16
0
Weeks
Includes death, MI resuscitated cardiac arrest,
recurrent symptomatic myocardial ischemia
requiring emergency rehospitalization.
Schwartz GG et al. JAMA 20012851711-1718
17
HMG-CoA Reductase Inhibitor Secondary Prevention
Pravastatin or Atorvastatin Evaluation and
Infection Therapy (PROVE-IT)TIMI 22 Study
4,162 pts with an ACS randomized to atorvastatin
(80 mg) or pravastatin (40 mg) for 24
months Acute intensive treatment
significantly reduces event rates
30
Atorvastatin Pravastatin
16 RRR
25
20
Recurrent MI, cardiac death, UA,
revascularization, or stroke
15
10
5
P 0.005
0
3 6 9 12 15 18 21 24 27
30
Follow-up (months)
ACSAcute coronary syndrome, CVCardiovascular,
MIMyocardial infarction, UAUnstable angina
Cannon CP et al. NEJM 20043501495-1504
18
HMG-CoA Reductase Inhibitor Secondary Prevention
Aggrastat to Zocor (A to Z) Trial
4,162 patients with an ACS randomized to
simvastatin (80 mg) or simvastatin (20 mg) for 24
months Acute intensive treatment
produces a trend towards reduced cardiovascular
events
Placebo Simvastatin 20 mg/day Simvastatin 40/80
mg/day
HR0.89, P0.14
Includes CV death, MI, readmission for an ACS,
and CVA
de Lemos JA et al. JAMA 20042921307-1316
19
HMG-CoA Reductase Inhibitor Secondary Prevention
Scandinavian Simvastatin Survival Study (4S)
4,444 patients with angina pectoris or previous
MI randomized to simvastatin (20-40 mg) or
placebo for 5.4 years Statins provide
significant benefit in those with average LDL-C
levels
30 RRR
11.5
12
8.2
8
Mortality ()
4
Plt0.001
0
Placebo
Simvastatin
MIMyocardial infarction, RRRRelative risk
reduction
4S Group. Lancet 199434413831389
20
HMG-CoA Reductase Inhibitor Secondary Prevention
Cholesterol and Recurrent Events (CARE) Study
4,159 patients with a history of MI randomized to
pravastatin (40 mg) or placebo for 5
years Statins provide significant
benefit in those with average cholesterol levels
24 RRR
15
13.2
10.2
10
Rate of MI or CHD death ()
5
P0.003
0
Placebo
Pravastatin
CHDCoronary heart disease, MIMyocardial
infarction, RRRRelative risk reduction
Sacks FM et al. NEJM 199633510011009
21
HMG-CoA Reductase Inhibitor Secondary Prevention
Long-term Intervention with Pravastatin in
Ischemic Disease (LIPID) Study
9,014 patients with a history of MI or
hospitalization for unstable angina randomized to
pravastatin (40 mg) or placebo for 6.1
years Statins provide significant
benefit across a broad range of cholesterol levels
24 RRR
8.3
9
6.4
6
CHD Death ()
3
Plt0.001
0
Placebo
Pravastatin
CHDCoronary heart disease, MIMyocardial
infarction, RRRRelative risk reduction
LIPID Study Group. NEJM 199833913491357
22
HMG-CoA Reductase Inhibitor Secondary Prevention
Heart Protection Study (HPS)
20,536 patients with CAD, other occlusive
arterial disease, or DM randomized to
simvastatin (40 mg) or placebo for 5.5
years Statins provide significant
benefit across a broad range of LDL-C levels
Event Rate Ratio (95 CI)
Baseline LDL-C (mg/dL) Statin (n 10,269) Placebo (n 10,267)
lt100 282 (16.4) 358 (21.0)
100129 668 (18.9) 871 (24.7)
?130 1083 (21.6) 1356 (26.9)
All patients 2033 (19.8) 2585 (25.2)
Statin Better
Statin Worse
0.76 (0.720.81) Plt0.0001
CADCoronary artery disease, CIConfidence
interval, DMDiabetes mellitus,
HPS Collaborative Group. Lancet 20023607-22
23
HMG-CoA Reductase Inhibitor Secondary Prevention
Prospective Study of Pravastatin in the Elderly
at Risk (PROSPER)
5,804 patients aged 70-82 years with a history
of, or risk factors for, vascular disease
randomized to pravastatin (40 mg) or placebo for
3.2 years Statins provide benefit in
older men
Placebo Pravastatin
20
CHD death, non-fatal MI, stroke ()
10
15 RRR, P0.014
0
0
1
2
3
4
Years
CHDCoronary heart disease, MIMyocardial
infarction, RRRRelative risk reduction
Shepherd J et al. Lancet 20023601623-1630
24
HMG-CoA Reductase Inhibitor Secondary Prevention
Treating to New Targets (TNT) Trial
10,001 patients with stable CHD randomized to
atorvastatin (80 mg) or atorvastatin (10 mg) for
4.9 years High-dose statins provide
benefit in chronic CHD
0.15
Atorvastatin (10 mg) Atorvastatin (80 mg)
22 RRR
0.10
Major CV Event ()
0.05
Plt0.001
0.00
Years
CHDCoronary heart disease, CVCardiovascular,
MIMyocardial infarction, RRRRelative risk
reduction
Includes CHD death, nonfatal MI, resuscitation
after cardiac arrest, or stroke
LaRosa JC et al. NEJM 20053521425-35
25
HMG-CoA Reductase Inhibitor Secondary Prevention
Incremental Decrease in End Points Through
Aggressive Lipid Lowering (IDEAL) Trial
8,888 patients with a history of acute MI
randomized to atorvastatin (80 mg) or simvastatin
(20 mg) for 5 years High-dose statins
provide a strong trend towards benefit after a MI
Simvastatin (20 mg) Atorvastatin (80 mg)
12
8
Cumulative Hazard ()
4
HR0.89, P0.07
0
1
2
3
4
5
Years Since Randomization
HRHazard ratio, MIMyocardial infarction
Includes coronary death, hospitalization for
nonfatal acute MI, or cardiac arrest with
resuscitation
Pedersen et al. JAMA 20052942437-2445
26
HMG-CoA Reductase Inhibitor Secondary Prevention
Relationship between LDL-C Levels and Event Rates
in Secondary Prevention Statin Trials of Patients
with Stable CHD
30
4S
Statin Placebo
25
4S
20
LIPID
Event ()
LIPID
15
CARE
CARE
HPS
10
HPS
TNT (atorvastatin 10 mg/d)
TNT (atorvastatin 80 mg/d)
5
0
0
70
90
110
130
150
170
190
210
LDL-C (mg/dL)
CARECholesterol and Recurrent Events Trial,
HPSHeart Protection Study, LIPIDLong-term
Intervention with Pravastatin in Ischaemic
Disease 4SScandinavian Simvastatin Survival
Study, TNTTreating to New Targets
LDL-CLow density lipoprotein cholesterol
LaRosa JC et al. NEJM 20053521425-1435
27
HMG-CoA Reductase Inhibitor Intensive Therapy
SI conversion factor To convert LDL-C to mmol/L,
multiply by 0.0259
ACSAcute coronary syndrome, CADCoronary artery
disease, CHDCoronary heart disease, LDL-CLow
density lipoprotein cholesterol, MIMyocardial
infarction, RRRelative reduction
Cannon CP et al. JAMA 20052942492-2494
28
HMG-CoA Reductase Inhibitor Adverse Effects
74,102 subjects in 35 randomized clinical trials
with statins

• 1.4 incidence of elevated hepatic transaminases
  (1.1 incidence in control arm)
• Dose-dependent phenomenon that is usually
  reversible

Hepatocyte

• 15.4 incidence of myalgias (18.7 incidence in
  control arm)
• 0.9 incidence of myositis (0.4 incidence in
  control arm)
• 0.2 incidence of rhabdomyolysis (0.1 incidence
  in control arm)

Skeletal myocyte
The rate of myalgias leading to discontinuation
of atorvastatin in the TNT trial was 4.8 and
4.7 in the 80 mg and 10 mg arms, respectively.
Kashani A et al. Circulation 20061142788-97
29
HMG-CoA Reductase Inhibitor Adverse Effects
Risk Factors for the Development of Myopathy
Concomitant Use of Meds
Fibrate
Nicotinic acid (Rarely)
Cyclosporine
Antifungal azoles
Macrolide antibiotics
HIV protease inhibitors
Nefazadone
Verapamil, Amiodarone
Other Conditions
Advanced age (especially gt80 years)
Women gt Men especially at older age
Small body frame, frailty
Multisystem disease
Multiple medications
Perioperative period
Alcohol abuse
Grapefruit juice (gt1 quart/day)
General term to describe diseases of
muscles Itraconazole, Ketoconazole Erythromycin
, Clarithromycin Chronic renal insufficiency,
especially from diabetes mellitus
Pasternak RC et al. Circulation 20021061024-1028
30
Bile Acid Sequestrant Mechanism of Action

• ? Cholesterol 7-? hydroxylase
• Conversion of cholesterol to BA
• BA Secretion

Bile Acid Enterohepatic Circulation
Terminal Ileum

• LDL Receptors
• VLDL and LDL removal

Reabsorption of bile acids

• BA Excretion

? LDL-C
BABile acid, LDL-CLow density lipoprotein
cholesterol, VLDLVery low density lipoprotein
cholesterol
31
Bile Acid Sequestrant Efficacy at Reducing LDL-C
TG
HDL-C
LDL-C

Change from baselineat week 24

Plt0.001 vs placebo P0.04 vs placebo
Insull W et al. Mayo Clin Proc 200176971-82
32
Bile Acid Sequestrant Primary Prevention
Lipid Research Clinics-Coronary Primary
Prevention Trial (LRC-CPPT)
3,806 men with primary hypercholesterolemia
randomized to cholestyramine (24 grams) or
placebo for 7.4 years Bile acid
sequestrants provide benefit in those with high
cholesterol levels
19 RRR
8.6
9
7.0
6
Rate of MI or CHD death ()
3
Plt0.05
0
Placebo
Cholestyramine
CHDCoronary heart disease, MIMyocardial
infarction, RRRRelative risk reduction
The LRC-CPPT Investigators. JAMA 1984251351-64
33
Ezetimibe Mechanism of Action
Production in liver
Absorption from intestine
Dietary cholesterol
Bloodstream
LDL-C
VLDL
Biliary cholesterol
Cholesterolsynthesis
Chylomicrons
Fecal sterols and neutral sterols
34
Ezetimibe Efficacy at Reducing LDL-C
Pooled Phase III Study Results
LDL-C
Triglycerides
HDL-C
5
1.0
1
0
0
2
5
Mean change frombaseline to week 12
8
10
15
18
20
Median change
Knopp RH. Int J Clin Pract 200357363-8
35
Dietary Adjuncts Efficacy at Reducing LDL-C
Therapy Dose (g/day) Effect
Dietary soluble fiber 2-8 ? LDL-C 5-10
Soy protein 20-30 ? LDL-C 5-7
Stanol esters 1.5-4 ? LDL-C 10-15
Jones PJ. Curr Atheroscler Rep 19991230-235 Lich
tenstein AH. Curr Atheroscler Rep
19991210-214 Rambjor GS et al. Lipids
199631S45-S49 Ripsin CM et al. JAMA
19922673317-3325
36
Diet Evidence Effect on Lipid Parameters and CRP
46 dyslipidemic patients randomized to a low fat
diet, a low fat diet and lovastatin (20 mg), or a
dietary portfolio for 4 weeks A
diversified diet improves lipid parameters and
CRP levels
30
LDL-C
LDL-CHDL-C
CRP
20
10
Low fat diet
0
Statin
Change from Baseline ()
-10
Dietary portfolio
-20
-30
-40
-50
0
2
4
0
2
4
0
2
4
Weeks
Weeks
Weeks
Enriched in plant sterols, soy protein, viscous
fiber, and almonds
Jenkins DJ et al. JAMA 2003290502-10
37
Nicotinic Acid Mechanism of Action
Mobilization of FFA
Apo B
Serum VLDL results in reduced lipolysis to LDL
VLDL
VLDL
TG synthesis
VLDL secretion
Serum LDL
HDL
Liver
Circulation
Hepatocyte
Systemic Circulation
Decreased hepatic production of VLDL and uptake
of apolipoprotein A-1 results in reduced LDL-C
levels and increased HDL-C levels
FFAFree fatty acids, HDLHigh density
lipoprotein, LDLLow density lipoprotein,
TGTriglyceride, VLDLVery low density lipoprotein
38
Nicotinic Acid Efficacy at Raising HDL-C
30
30
HDL-C
26
22
15
10
9
Change from Baseline
14
17
5
21
22
LDL-C
11
28
35
TG
39
44
500
1000
1500
2000
2500
Dose (mg)
3000
Goldberg A et al. Am J Cardiol 2000851100-1105
39
Nicotinic Acid Secondary Prevention
Coronary Drug Project (CDP)
8,341 men with previous myocardial infarction
randomized to nicotinic acid (3 grams) or placebo
for 15 years Nicotinic acid
provides long-term benefit following a MI
100
90
Nicotinic Acid Placebo
80
70
Survival ()
60
Nicotinic acid stopped
50
40
P0.0012
14
16
6
10
12
0
4
8
2
Years of follow-up
MIMyocardial infarction
Canner PL et al. JACC 1986812451255
40
Nicotinic Acid Secondary Prevention
HDL-Atherosclerosis Treatment Study (HATS)
160 men with CAD, low HDL-C, and normal LDL-C
randomized to simvastatin (10-20 mg) niacin
(1000 mg bid), simvastatin (10-20 mg) niacin
(1000 mg bid) antioxidants, antioxidants, or
placebo for 3 years Simvastatin
niacin benefits men with CAD and low HDL-C

Includes cardiovascular death, MI, stroke, or
need for coronary revascularization
Brown BG et al. NEJM 20013451583-92
41
CHD Risk According to Triglyceride Levels
Framingham Study
3.0
Men
2.5
Women
2.0
RR
1.5
1.0
0.5
0.0
50
100
150
200
250
300
350
400
Triglyceride Level (mg/dL)
CHDCoronary heart disease, RRRelative Risk
Castelli WP. Can J Cardiol 198845A-10A
42
Fibrate Mechanism of Action
Fibrate

TG
LPL

VLDL
Intestine
IDL
LDL-R
CE
FC
FC
CE
Liver
Nascent HDL
Macrophage
Mature HDL
CECholesterol ester, FCFree cholesterol,
HDLHigh density lipoprotein, IDLIntermediate
density lipoprotein, LDL-RLow density
lipoprotein receptor, LPLLipoprotein lipase,
TGTriglyceride,
43
Fibrate Efficacy at Reducing Triglyceride
147 patients with type IV/V hyperlipoproteinemia
randomized to fenofibrate (100 mg three times
daily) or placebo for 8 weeks
TG 350499 mg/dL
TG 5001500 mg/dL
50
45
40
30
23
20
20
15
10
TG
TG
0
LDL
HDL
HDL
LDL

Mean change from baseline
-10
-20
-30
-40
-50
-46
-55
-60
TGTriglyceride level
Goldberg AC et al. Clin Ther 1989116983
44
Fibrate Primary and Secondary Prevention
42
Rx Placebo
22
22
22
9
17
15
13.6
66
CHD Death/Nonfatal MI
13
34
8
4.1
2.7
2.7
HHS
HHS
BIP
BIP
VA-HIT
PRIMARY PREVENTION
SECONDARY PREVENTION
Post hoc analysis of subgroup with TG gt200 mg/dL
and HDL-C lt42 mg/dL Post hoc analysis of
subgroup with TG ?200 mg/dL and HDL-C lt35
mg/dL Difference between placebo and Rx for
primary endpoint was statistically significant (p
lt 0.05)
Frick MH et al. NEJM 19873171237-1245 Manninen
V et al. Circulation 19928537-45 BIP Study
Group. Circulation 200010221-27 Rubins HB et
al. NEJM 1999341410-418
45
Fibrate Secondary Prevention
Fenofibrate Intervention and Event Lowering in
Diabetes (FIELD)
9,795 diabetic patients randomized to fenofibrate
(200 mg) or placebo for 5 yrs
Fenofibrate fails to provide significant
additional benefit
11 RRR
9
5.9
5.2
6
CHD Death or Nonfatal MI ()
3
P0.16
0
Placebo
Fenofibrate
CHDCoronary heart disease, MIMyocardial
infarction
Unadjusted for concomitant statin use
Keech A et al. Lancet 20053661849-61
46
Cholesterol Management Pharmacotherapy
HDL-CHigh-density lipoprotein cholesterol,
LDL-CLow-density lipoprotein cholesterol,
TCTotal cholesterol, TGTriglycerides Daily
dose of 40mg of each drug, excluding rosuvastatin
47
w-3 Fatty Acids Efficacy at Reducing Triglyceride
27 patients with hypertriglyceridemia and low
HDL-C treated with n-3 fatty acid (4 grams/day)
for 7 months
Total Cholesterol
Triglyceride
0
-10
-20
Reduction
-21
-30
-40
-46
-50
Plt0.05
Abe Y et al. Arterioscler Thromb Vasc Biol
199818723-731
48
w-3 Fatty Acids Primary and Secondary Prevention
JELIS Trial
18,645 patients with hypercholesterolemia
randomized to EPA (1800 mg) with a statin or a
statin alone for 5 years EPA provides
additional cardiovascular benefit to those on
statin therapy, particularly in secondary
prevention
Composite of cardiac death, myocardial
infarction, angina, PCI, or CABG
Yokoyama M et al. Lancet. 20073691090-8
49
w-3 Fatty Acids Secondary Prevention
Diet and Reinfarction Trial (DART) Gruppo
Italiano per lo Studio della Sopravvivenza
nellInfarto miocardico (GISSI)
N-3 Fatty Acids Placebo
All cause mortality ()
DART (n3,482)
GISSI (n11,324)
w-3 fatty acids reduce mortality post MI
Post myocardial infarction
Burr ML et al. Lancet 19892757-761 GISSI
Investigators. Lancet 1999354447-455
50
CHD Risk According to HDL-C Levels
Framingham 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)
CHDCoronary heart disease, HDL-CHigh-density
lipoprotein cholesterol
Kannel WB. Am J Cardiol 1983529B12B
51
Risk Profile Assessment for LDL-C Lowering
A risk assessment tool is needed for individuals
with gt2 RFs
10-year CHD Risk
CAD or Risk Equivalent
CADCoronary artery disease, CHDCoronary heart
disease, DMDiabetes mellitus, RFRisk factor
Such as the Framingham Risk Score (FRS)
Includes DM, non-coronary atherosclerotic
vascular disease, and gt20 10-year CHD risk by
the FRS
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-97
52
Framingham Risk Score Men
Step 1 Age Points
Step 5 Smoking Status Points
Step 4 SBP Points
Years Points
20-34 -9
35-39 -4
40-44 0
45-49 3
50-54 6
55-59 8
60-64 10
65-69 11
70-74 12
75-79 13
Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79
Nonsmoker 0 0 0 0 0
Smoker 8 5 3 1 1
SBP (mmHg) If untreated If treated
lt120 0 0
120-129 0 1
130-139 1 2
140-159 1 2
gt160 2 3
Step 6 Sum of Points
Age
Total Cholesterol
HDL-C
Systolic Blood Pressure
Smoking Status
Point Total
Step 2 Total Cholesterol Points
Step 7 10-year CHD Risk
TC (mg/dl) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79
lt160 0 0 0 0 0
160-199 4 3 2 1 0
200-239 7 5 3 1 0
240-279 9 6 4 2 1
gt280 11 8 5 3 1
Point Total 10-year Risk Point Total 10-year Risk Point Total 10-year Risk
lt0 lt1 6 2 13 12
0 1 7 3 14 16
1 1 8 4 15 20
2 1 9 5 16 25
3 1 10 6 gt17 gt30
4 1 11 8
5 2 12 10
Step 3 HDL-C Points
HDL-C (mg/dl) Points
gt60 -1
50-59 0
40-49 1
lt40 2
53
Framingham Risk Score Women
Step 1 Age Points
Step 4 SBP Points
Step 5 Smoking Status Points
Years Points
20-34 -7
35-39 -3
40-44 0
45-49 3
50-54 6
55-59 8
60-64 10
65-69 12
70-74 14
75-79 16
SBP (mmHg) If untreated If treated
lt120 0 0
120-129 1 3
130-139 2 4
140-159 3 5
gt160 4 6
Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79
Nonsmoker 0 0 0 0 0
Smoker 9 7 4 2 1
Step 6 Sum of Points
Age
Total Cholesterol
HDL-C
Systolic Blood Pressure
Smoking Status
Point Total
Step 2 Total Cholesterol Points
Step 7 10-year CHD Risk
TC (mg/dl) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79
lt160 0 0 0 0 0
160-199 4 3 2 1 1
200-239 8 6 4 2 1
240-279 11 8 5 3 2
gt280 13 10 7 4 2
Point Total 10-year Risk Point Total 10-year Risk Point Total 10-year Risk
lt9 lt1 15 3 22 17
9 1 16 4 23 22
10 1 17 5 24 27
11 1 18 6 gt25 gt30
12 1 19 8
13 2 20 11
14 2 21 14
Step 3 HDL-C Points
HDL-C (mg/dl) Points
gt60 -1
50-59 0
40-49 1
lt40 2
54
ATP III LDL-C Goals and Cut-points for Drug
Therapy
Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy
High risk CHD or CHD risk equivalents (10-year risk gt20) lt100 mg/dL (optional goal lt70) ?100 mg/dL gt100 mg/dL (lt100 mg/dL consider drug options)
Moderately high risk 2 risk factors (10-year risk 10 to 20) lt130 mg/dL (optional goal lt100) ?130 mg/dL gt130 mg/dL (100-129 mg/dL consider drug options)
Moderate risk 2 risk factors (10 year risk lt10) lt130 mg/dL ?130 mg/dL gt160 mg/dL
Lower risk 0-1 risk factor lt160 mg/dL ?160 mg/dL gt190 mg/dL (160-189 mg/dL LDL-lowering drug optional)
Risk factors for CHD include cigarette smoking,
hypertension (blood pressure gt140/90 mmHg or on
antihypertensive medication, HDL-C lt40 mg/dl (gt60
mg/dl is a negative risk factor), family history
of premature CHD, age gt45 years in men or gt55
years in women
ATPAdult Treatment Panel, CHDCoronary heart
disease, LDL-CLow-density lipoprotein
cholesterol, TLCTherapeutic lifestyle changes
Grundy S et al. Circulation 2004110227-39
55
ATP III Classification of Other Lipoprotein Levels
Total Cholesterol
HDL-Cholesterol
Level (mg/dl) Classification
lt200 Desirable
200-239 Borderline High
gt240 High
Level (mg/dl) Classification
lt40 Desirable
40-50 Borderline High
gt50 High
Triglyceride
Level (mg/dl) Classification
lt150 Normal
150-199 Borderline High
200-499 High
gt500 Very High
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-97
56
Cholesterol Management Guidelines (Continued)
As set forth by the NCEP

• Obtain a fasting lipid profile in all patients.
  For those with an MI, a fasting lipid profile
  should be obtained within 24 hours of admission.
• Start therapeutic lifestyle changes in all
  patients, including
• Reduced intake of saturated fat (lt7 of total
  calories) and cholesterol (lt200 mg/day)
• Addition of plant stanols/sterols (2 g/day) and
  viscous fiber (10-25 g/day) to enhance LDL-C
  lowering
• Weight reduction
• Increased physical activity

LDL-CLow density lipoprotein cholesterol,
NCEPNational Cholesterol Education Program
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-97
57
Cholesterol Management Guidelines (Continued)
As set forth by the NCEP
HMG-CoA reductase inhibitors (statins) are used
first-line to achieve the LDL-C goal If the
LDL-C level is above goal, statin therapy should
be intensified the addition of a second LDL-C
lowering agent If the TG level is gt150 mg/dl or
the HDL-C level is lt40 mg/dl, weight loss,
physical activity, and smoking cessation should
be emphasized If the TG level is 200-499 mg/dl
after initiation of LDL-C lowering therapy,
nicotinic acid or a fibrate should be
considered If the TG level is gt500 mg/dl,
nicotinic acid or a fibrate should be considered
before starting LDL-C lowering therapy
HDL-CHigh density lipoprotein cholesterol,
LDL-CLow density lipoprotein cholesterol,
NCEPNational Cholesterol Education Program,
TGTriglyceride
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-97
58
Cholesterol Management Guidelines
Secondary Prevention
Restriction of saturated fat (lt7 of total
calories), trans-fatty acids, and cholesterol
(lt200 mg/day) in all patients Promotion of daily
physical activity and weight management in all
patients Increase in w-3 fatty acid consumption
in all patients
59
Cholesterol Management Guidelines (Continued)
Secondary Prevention
Initiation or intensification of LDL-C lowering
drug therapy in those with a baseline or
on-treatment LDL-C level gt100 mg/dl Intensificati
on of LDL-C lowering drug therapy to achieve a
LDL-C lt70 mg/dl Initiation of LDL-C lowering
drug therapy in those with a baseline LDL-C level
of 70-100 mg/dl to achieve a LDL-C level lt70 mg/dl
LDL-CLow density lipoprotein cholesterol
60
Cholesterol Management Guidelines (Continued)
Secondary Prevention
Intensification of LDL-C lowering drug therapy
(Class I, Level B) or addition of a fibrate or
niacin (Class I, Level B in men Class I, Level C
in women) in those with a TG level of 200-499
mg/dl Initiation of a fibrate or niacin before
LDL-C lowering drug therapy in those with a TG
level gt500 mg/dl
LDL-CLow density lipoprotein cholesterol,
TGTriglyceride
61
Cholesterol Management Guidelines (Continued)
Secondary Prevention
Reduction of non-HDL-cholesterol to lt130 mg/dl in
those with a TG level of 200-499
mg/dl Reduction of non-HDL-cholesterol to lt100
mg/dl in those with a TG level of 200-499 mg/dl
HDL-CHigh density lipoprotein cholesterol,
LDL-CLow density lipoprotein cholesterol,
TGTriglyceride
62
Cholesterol Management Guidelines (Continued)
Secondary Prevention
Therapeutic options to reduce non-HDL-cholesterol
include Intensification of LDL-C lowering drug
therapy Niacin (after initiation of LDL-C
lowering drug therapy) Fibrate therapy (after
initiation of LDL-C lowering drug therapy)
HDL-CHigh density lipoprotein cholesterol,
LDL-CLow density lipoprotein cholesterol