The Evidence for Current Cardiovascular Disease Prevention Guidelines: Cholesterol, Cholesterol Therapies, and Cholesterol Guidelines
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The Evidence for Current
Cardiovascular Disease Prevention
Guidelines:
Cholesterol, Cholesterol Therapies,
and Cholesterol Guidelines
Ty J. Gluckman, Ryan J. Tedford, Andrew P. DeFilippis, James
Mudd, Catherine Campbell, & Roger S. Blumenthal
The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease
Classification of Recommendations
and Levels of Evidence
*Data available from clinical trials or
registries about the usefulness/efficacy in
different subpopulations, such as gender,
age, history of diabetes, history of prior
myocardial infarction, history of heart
failure, and prior aspirin use. A
recommendation with Level of Evidence B
or C does not imply that the
recommendation is weak. Many important
clinical questions addressed in the
guidelines do not lend themselves to
clinical trials. Even though randomized
trials are not available, there may be a
very clear clinical consensus that a
particular test or therapy is useful or
effective.
†In 2003, the ACC/AHA Task Force on
Practice Guidelines developed a list of
suggested phrases to use when writing
recommendations. All guideline
recommendations have been written in full
sentences that express a complete
thought, such that a recommendation,
even if separated and presented apart
from the rest of the document (including
headings above sets of
recommendations), would still convey the
full intent of the recommendation. It is
hoped that this will increase readers’
comprehension of the guidelines and will
allow queries at the individual
recommendation level.
Icons Representing the Classification and
Evidence Levels for Recommendations
I IIa IIb III I IIa IIb III I IIa IIb III
I IIa IIb III I IIa IIb III I IIa IIb III
I IIa IIb III I IIa IIb III I IIa IIb III
I IIa IIb III I IIa IIb III I IIa IIb III
Evidence for Current Cardiovascular Disease
Prevention Guidelines
Cholesterol, Cholesterol Therapies,
and Cholesterol Guidelines
Lipoprotein Classes
Chylomicrons, LDL HDL
VLDL, and
their catabolic
remnants
> 30 nm 20–22 nm 9–15 nm
Potentially Potentially
pro-inflammatory anti-inflammatory
Sources:
P. Barter. Role of Lipoproteins in Inflammation presentation, 2001. Available at
http://www.lipidsonline.org/slides/slide01.cfm?&tk=18&dpg=3&x=293&43416.
Doi H et al. Circulation 2000;102:670-676
Colome C et al. Atherosclerosis 2000;149:295-302
Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994
Role of Lipoproteins in Atherogenesis
HDL High plasma Endothelial
LDL injury
LDL
+ LDL infiltration Adherence
VLDL into intima of platelets
LCAT
APO-A1
Oxidative Release
Liver modification of PDGF
of LDL Other
+ growth
Cholesterol Macrophages factors
excreted Advanced
Foam cells
fibrocalcific
Fatty streak lesion
APO-A1=Apolipoprotein A1, HDL=High density lipoprotein,
LCAT=Lecithin cholesterol acyltransferase, LDL=Low density lipoprotein,
PDGF=Platelet-derived growth factor, VLDL=Very low density lipoproteinAttributable Risk Factors
for a First Myocardial Infarction
100 INTERHEART Study 90
80
PAR (%)
60
50
40 36 33
20
20
18
14 12 10
7
0
Smoking Fruits/ Exercise Alcohol Hyper- Diabetes Abdominal Psycho- Lipids All 9 risk
Veg tension obesity social factors
Lifestyle factors
N = 15,152 patients and 14,820 controls in 52 countries
MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors)
Source: Yusuf S et al. Lancet. 2004;364:937-52.Change in Total Cholesterol Levels
in the United States Over Time
National Health and Nutrition Examination Survey (NHANES)
100%
90%
Total Cholesterol mg/dl (mmol/L)
80%
age-adjusted percentage
70%
60%
50%
>240 mg/dL (>6.21 mmol/L)
40% 200-240 mg/dL (5.17-6.21 mmol/L)
30%CHD Risk According to LDL-C Level
Heart Disease (Log Scale) 3.7
Relative Risk for Coronary
2.9
2.2
1.7
1.3
1.0
40 70 100 130 160 190
LDL-Cholesterol (mg/dL)
CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol
Source: Grundy S et al. Circulation 2004;110:227-39Therapies to Lower Levels of LDL-C
Class Drug(s)
3-Hydroxy-3-Methylglutaryl Coenzyme A Atorvastatin (Lipitor)
(HMG-CoA) reductase inhibitors [Statins] Fluvastatin (Lescol XL)
Lovastatin (generic and Mevacor)
Pitavastatin (Livalo)
Pravastatin (Pravachol)
Rosuvastatin (Crestor)
Simvastatin (Zocor)
Bile acid sequestrants Cholestyramine (generic and Questran)
Colesevelam (Welchol)
Colestipol (Colestid)
Cholesterol absorption inhibitor Ezetimibe (Zetia)
Nicotinic acid Niacin
Dietary Adjuncts Soluble fiber
Soy protein
Stanol estersHMG-CoA Reductase Inhibitor:
Mechanism of Action
Inhibition of the Cholesterol Biosynthetic Pathway
Squalene Dolichol
HMG-CoA synthase
Reductase
Acetyl HMG- Mevalonate Farnesyl Squalene Cholesterol
CoA CoA pyrophosphate
Farnesyl-
transferase
E,E,E-
Geranylgeranyl
Farnesylated pyrophosphate
proteins
Geranylgeranylated Ubiquinones
proteinsHMG-CoA Reductase Inhibitor:
Mechanism of Action
Cholesterol VLDL
synthesis
LDL receptor Apo B
VLDLR LDL-R–mediated hepatic
(B–E receptor) uptake of LDL and VLDL
synthesis Apo E remnants
Intracellular Serum LDL-C
Cholesterol Apo B
LDL Serum VLDL remnants
Serum IDL
Hepatocyte Systemic Circulation
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
Source: McKenney JM. Selecting Successful Lipid-lowering Treatment presentation, 2002. Available at
http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=4.HMG-CoA Reductase Inhibitor:
Dose-Dependent Effect
The Rule of 6’s
Lovastatin 20/80 28 12
Pravastatin 20/40 27 6
Simvastatin 20/80 35 12
Fluvastatin 20/80 19 12
Atorvastatin 10/80 37 18
0 10 20 30 40 50 60
Reduction of LDL Cholesterol (%)
Each doubling of the statin dose produces an approximate 6%
reduction in the LDL-C level
Source: Illingworth DR. Med Clin North Am 2000;84:23-42HMG-CoA Reductase Inhibitor:
Reduction in LDL-C
A Meta-analysis of 164 Trials*†
Statin 10 mg/d 20 mg/d 40 mg/d 80 mg/d
Atorvastatin 69 (37) 80 (43) 91 (49) 102 (55)
Fluvastatin 29 (15) 39 (21) 50 (27) 61 (33)
Lovastatin‡ 39 (21) 54 (29) 68 (37) 83 (45)
Pravastatin 37 (20) 45 (24) 53 (29) 62 (33)
Rosuvastatin 80 (43) 90 (48) 99 (53) 108 (58)
Simvastatin 51 (27) 60 (32) 69 (37) 78 (42)
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
FDA=Food and Drug Administration, LDL-C=Low density lipoprotein
cholesterol, Rx=Treatment
Source: Law MR et al. BMJ 2003;326:1423-1427HMG-CoA Reductase Inhibitor:
Chronological Order of Event Driven Trials
Study populations:
Primary prevention
Acute coronary syndromes (Secondary prevention)
Chronic Coronary heart disease (Secondary prevention)
1994 4S 2002 PROSPER
1995 WOSCOPS 2002 ALLHAT-LLA
1996 CARE 2002 ASCOT-LLA
1998 AFCAPS/TEXCAPS 2004 PROVE-IT
1998 LIPID 2004 A to Z
2001 MIRACL 2005 TNT
2002 HPS 2005 IDEAL
2008 JUPITER
*Trials with clinical outcomesHMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
West of Scotland Coronary Prevention Study
(WOSCOPS) randomized to pravastatin
6,595 men with moderate hypercholesterolemia
(40 mg) or placebo for 5 years
31% RRR
9
7.5
Rate of MI or CHD
death (%)
6 5.3
3
PHMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
West of Scotland Coronary Prevention Study
Long-term follow-up at 5 (WOSCOPS)
and 10 years after conclusion of the study
Risk of MI or CHD death (%)
A statin provides long-term benefit in those with average cholesterol levels
CHD=Coronary heart disease, MI=Myocardial infarction,
RRR=Relative risk reduction
Source: Ford I et al. NEJM 2007;357:1477-86HMG-CoA Reductase Inhibitor Evidence:
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
37% RRR
6 5.5
Rate of MI, unstable
angina, or SCD (%)
4 3.5
2
PHMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial—Lipid Lowering Arm (ALLHAT-LLA)
10,355 patients with HTN and >1 CHD risk factor randomized to pravastatin
(40 mg) or usual care for 5 years
18
Pravastatin
Cumulative rate %
15 Usual care
12
9 32% cross-over
among patients
6
with CHD
3 RR, 0.99; P=0.88
0
1 2 3 4 5 6
Years
The failure to demonstrate benefit with a statin may be the result of a high
rate of cross over
CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk
Source: ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Anglo-Scandinavian Cardiac Outcomes Trial—Lipid
Lowering Arm (ASCOT-LLA)
10,305 patients with HTN randomized to atorvastatin (10 mg) or
placebo for 5 years
4
Cumulative incidence of
Atorvastatin 90 mg/dl*
MI and fatal CHD (%)
3 Placebo 126 mg/dl* 36% RRR
2
1
P=0.0005
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
*Post-treatment LDL-C level Follow-up (yr)
A statin provides significant benefit in moderate- to high-risk
individuals by lowering LDL-C levels below current goals
CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol,
RR=Relative risk
Source: Sever PS et al. Lancet. 2003;361:1149-1158HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Relationship between LDL-C Levels and Event Rates in
Select Primary Prevention Statin Trials
10
Statin
8 Placebo
CHD event rate (%)
WOSCOPS
WOSCOPS
6
AFCAPS
AFCAPS
4
ASCOT
2
ASCOT
0 P=0.0019
–1
55 75 95 115 135 155 175 195
LDL cholesterol (mg/dL)
AFCAPS= Air Force/Texas Coronary Atherosclerosis Prevention Study,
ASCOT= Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering
Arm, WOSCOPS= West of Scotland Coronary Prevention Study
Source: O’Keefe JH Jr et al. JACC 2004;43:2142-6HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Management of Elevated Cholesterol in the Primary
Prevention Group of Adult Japanese (MEGA) Trial
7,832 men (age 40-70 years) and postmenopausal women (up to age 70
years) with total cholesterol levels of 220-270 mg/dL randomized to
pravastatin (10-20 mg) or placebo for 5.3 years
33% RRR
Number of adverse CV
6
5.0
events* per 1000
person years
4
3.3
2
P=0.01
0
Placebo Pravastatin
A statin provides benefit in those with high cholesterol levels
*Composite of cardiac and sudden death, myocardial infarction, angina, and
cardiac or vascular intervention
Source: Nakamura H et al. Lancet 2006;368:1155-63HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Justification for the Use of Statins in Prevention: An
Intervention Trial Evaluating Rosuvastatin (JUPITER)
17,802 men (>50 years) and women (>60 years) with LDL-C 2 mg/L randomized to rosuvastatin (20 mg) or placebo for up
to 5 years*
death, MI, CVA, hospitalization
0.08
Cumulative incidence of CV
arterial revascularization
for unstable angina, and
Rosuvastatin
Placebo
44% RRR
0.04
PHMG-CoA Reductase Inhibitor Evidence:
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
Combined cardiovascular
17.4%
15 Placebo
14.8%
event rate (%)*
Atorvastatin
10
5
RR=0.84, P=0.048
0
0 4 8 12 16
Weeks
Acute intensive statin therapy provides significant CV benefit
*Includes death, MI resuscitated cardiac arrest, recurrent symptomatic
myocardial ischemia requiring emergency rehospitalization.
Source: Schwartz GG et al. JAMA 2001;285:1711-1718HMG-CoA Reductase Inhibitor Evidence:
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
UA, revascularization, or stroke
Recurrent MI, cardiac death,
30
Pravastatin 16% RRR
25
20 Atorvastatin
15
10
5
P =0.005
0
3 6 9 12 15 18 21 24 27 30
Follow-up (months)
Acute intensive statin therapy provides significant CV benefit
ACS=Acute coronary syndrome, CV=Cardiovascular,
MI=Myocardial infarction, UA=Unstable angina
Source: Cannon CP et al. NEJM 2004;350:1495-1504HMG-CoA Reductase Inhibitor Evidence:
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
20
Placebo + Simvastatin 20 mg/day
event rate (%)*
15
Cumulative
Simvastatin 40/80 mg/day
10
5
HR=0.89, P=0.14
0
0 4 8 12 16 20 24
Time from randomization (months)
Acute intensive statin therapy produces a trend towards CV benefit
*Includes CV death, MI, readmission for an ACS, and CVA
Source: de Lemos JA et al. JAMA 2004;292:1307-1316HMG-CoA Reductase Inhibitor Evidence:
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
30% RRR
12 11.5
8.2
Mortality (%)
8
4
PHMG-CoA Reductase Inhibitor Evidence:
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
24% RRR
15 13.2
Rate of MI or CHD
10.2
death (%)
10
5
P=0.003
0
Placebo Pravastatin
A statin provides significant benefit in those with average cholesterol levels
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk
reduction
Srouce: Sacks FM et al. NEJM 1996;335:1001–1009HMG-CoA Reductase Inhibitor Evidence:
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
24% RRR
9 8.3
CHD Death (%)
6.4
6
3
PHMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Heart Protection Study (HPS)
Event Rate Ratio (95% CI)
Baseline Statin Placebo Statin Better Statin Worse
LDL-C (mg/dL) (n = 10,269) (n = 10,267)HMG-CoA Reductase Inhibitor Evidence:
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
CHD death, non-fatal
20
MI, stroke (%)
Placebo
10 Pravastatin
0 15% RRR, P=0.014
0 1 2 3 4
Years
A statin provides CV benefit in older men
CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction,
RRR=Relative risk reduction
Source: Shepherd J et al. Lancet 2002;360:1623-1630HMG-CoA Reductase Inhibitor Evidence:
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
0.15
Major CV Event* (%)
Atorvastatin (10 mg) 22% RRR
0.10
Atorvastatin (80 mg)
0.05
PHMG-CoA Reductase Inhibitor Evidence:
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
12
Cumulative Hazard
Simvastatin (20 mg)
8
(%)
Atorvastatin (80 mg)
4
HR=0.89, P=0.07
0 1 2 3 4 5
Years Since Randomization
High-dose statin therapy provides a strong trend towards CV benefit after a MI
*Includes coronary death, hospitalization for nonfatal acute MI, or cardiac
arrest with resuscitation
HR=Hazard ratio, MI=Myocardial infarction
Source: Pedersen et al. JAMA 2005;294:2437-2445HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Relationship between LDL-C Levels and Event Rates in
Secondary Prevention Statin Trials of Patients with Stable CHD
30 Statin 4S
Placebo
25
4S
Event (%)
20
LIPID LIPID
15 CARE
CARE
HPS HPS
10
TNT (atorvastatin 10 mg/d)
5 TNT (atorvastatin 80 mg/d)
0
0 70 90 110 130 150 170 190 210
LDL-C (mg/dL)
CARE=Cholesterol and Recurrent Events Trial, HPS=Heart Protection Study,
LDL-C=Low denity lipoprotein cholesterol, LIPID=Long-term Intervention with
Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study,
TNT=Treating to New Targets
Source: LaRosa JC et al. NEJM 2005;352:1425-1435HMG-CoA Reductase Inhibitor Evidence:
Degree of Benefit in Prevention Types
Meta-analysis of randomized controlled trials
comparing risk reductions between primary and secondary prevention patients
Relative Absolute Number Needed
Risk Reduction Risk Reduction To Treat
Primary Secondary Primary Secondary Primary Secondary
Major CHD 29.2 20.8 1.66 2.4 60 33
events
Major CV 14.4 17.8 0.37 0.8 268 125
events
Nonfatal 31.7 NA 1.65 NA 61 NA
MI
PCI or 33.8 20.3 1.08 2.7 93 37
CABG
CABG=Coronary artery bypass graft surgery, CHD=Coronary heart
disease, CV=Cardiovascular, MI=Myocardial infarction, PCI=Percutaneous
coronary intervention
Source: Thavendiranathan, P. et al. Arch Intern Med 2006;166:2307-2313HMG-CoA Reductase Inhibitor Evidence:
Effect of Intensive Therapy
Magnitude of event reduction among trials of intensive statin therapy
Trial Population Duration LDL-C Reduction RR in Primary RR in MI or
(years) (mg/dL) End Point (%) CHD Death (%)
PROVE IT- ACS
2 33 16 16
TIMI 22 (N = 4162)
ACS
A to Z 2 14 11 15
(N = 4497)
Stable CAD
TNT 5 24 22 21
(N =10,001)
Stable CAD
IDEAL 5 23 11 11
(N = 8888)
Note: SI conversion factor: To convert LDL-C to mmol/L, multiply by 0.0259
ACS=Acute coronary syndrome, CAD=Coronary artery disease,
CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol,
MI=Myocardial infarction, RR=Relative reduction
Source: Cannon CP et al. JAMA 2005;294:2492-2494HMG-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.
Source: Kashani A et al. Circulation 2006;114:2788-97HMG-CoA Reductase Inhibitor:
Adverse Effects
Risk Factors for the Development of Myopathy*
Concomitant Use of Meds Other Conditions
Fibrate Advanced age (especially >80 years)
Nicotinic acid (Rarely) Women > Men especially at older age
Cyclosporine Small body frame, frailty
Antifungal azoles** Multisystem disease‡
Macrolide antibiotics† Multiple medications
HIV protease inhibitors Perioperative period
Nefazadone Alcohol abuse
Verapamil, Amiodarone Grapefruit juice (>1 quart/day)
**Itraconazole, Ketoconazole ‡Chronic renal insufficiency, especially from diabetes
†Erythromycin, Clarithromycin mellitus
*General term to describe diseases of muscles
Source: Pasternak RC et al. Circulation 2002;106:1024-1028Bile Acid Sequestrant:
Mechanism of Action
Cholesterol 7- hydroxylase
Conversion of cholesterol to BA
Gall Bladder BA Secretion
Bile Acid
Enterohepatic Circulation Liver
Terminal Ileum
LDL Receptors
Reabsorption of
VLDL and LDL removal
bile acids
BA Excretion
LDL-C
BA=Bile acid, LDL-C=Low density lipoprotein cholesterol,
VLDL=Very low density lipoprotein cholesterolBile Acid Sequestrant Evidence:
Efficacy at Reducing LDL-C
15 LDL-C HDL-C TG
% Change from baseline
10
10
† 5
5 3
at week 24
0
0
-1
-5
-10 Placebo
-15 *
Colesevelam 3.8 grams/day
-15
-20
*PBile Acid Sequestrant Evidence:
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
19% RRR
9 8.6
Rate of MI or CHD
7.0
death (%)
6
3
PEzetimibe:
Mechanism of Action
Production in liver Absorption from intestine
Bloodstream Dietary cholesterol
LDL-C VLDL
Biliary cholesterol
Cholesterol
synthesis Chylomicrons
Fecal sterols and neutral sterolsEzetimibe Evidence:
Efficacy at Reducing LDL-C
892 patients with primary hypercholesterolemia randomized
to ezetimibe (10 mg) or placebo for 12 weeks
LDL-C HDL-C Triglycerides
+5.7
+5
+0.4 +1.3
Mean % change from
baseline to week 12
0
–1.6
–5
–5.7
–10
–15
–16.9* Placebo
–20 Ezetimibe 10 mg
*pDietary Adjuncts Evidence:
Efficacy at Reducing LDL-C
Therapy Dose (g/day) Effect
Dietary soluble fiber 5-10 (psyllium) LDL-C 10-15%
Soy protein 20-30 LDL-C 5-7%
Stanol esters 1.5-2 LDL-C 15-20%
Sources:
Kwiterovich Jr PO. Pediatrics 1995;96:1005-9
Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214
Miettinen TA et al. Ann Med 2004;36:126-34CHD Risk According to HDL-C Level
Framingham Study
4.0 4.0
CHD risk ratio 3.0
2.0 2.0
1.0 1.0
0
25 45 65
HDL-C (mg/dL)
CHD=Coronary heart disease, HDL-C=High-density lipoprotein cholesterol
Source: Kannel WB. Am J Cardiol 1983;52:9B–12BNicotinic Acid:
Mechanism of Action
Mobilization of FFA
Apo B Serum VLDL
results in reduced
VLDL lipolysis to LDL
VLDL
TG
VLDL Serum LDL
synthesis
secretion
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
FFA=Free fatty acids, HDL=High density lipoprotein, LDL=Low density
lipoprotein, TG=Triglyceride, VLDL=Very low density lipoprotein
Source: McKenney JM. Selecting Successful Lipid-lowering Treatments presentation,
2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=14Nicotinic Acid Evidence:
Effect on Lipid Parameters
30% 30%
26% HDL-C
22%
Mean change from Baseline
30 15%
10%
20
10
–9%
0
–14%
–5% –17%
-10
–22% –21%
–11% LDL-C
-20
–28%
-30
–35%
-40
–39% TG
-50 –44%
Dose (mg) 500 1000 1500 2000 2500 3000
Source: Goldberg A et al. Am J Cardiol 2000;85:1100-1105Nicotinic Acid Evidence:
Secondary Prevention
Coronary Drug Project (CDP)
100
90
Survival (%)
80
70
Nicotinic Acid
60 Nicotinic acid
50 stopped Placebo
40
P=0.0012
0 2 4 6 8 10 12 14 16
Years of follow-up
MI=Myocardial infarction
Source: Canner PL et al. JACC 1986;8:1245–1255Nicotinic Acid Evidence:
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
**
A statin plus niacin provides benefit to men with CAD and low HDL-C levels
**Includes cardiovascular death, MI, stroke, or need for coronary
revascularization
Source: Brown BG et al. NEJM 2001;345:1583-92CHD Risk According to Triglyceride Levels
Meta-analysis of 29 prospective studies evaluating the risk of
CHD relative to triglyceride level (top third vs. bottom third)
An elevated triglyceride level is associated with increased CHD risk
CHD=Coronary heart disease
Source: Sarwar N et al. Circulation 2007;115:450-8Fibrate:
Mechanism of Action
Fibrate
TG +
LPL
+
VLDL
Intestine
LDL-R IDL
CE
CE FC FC
Liver Nascent
HDL Macrophage
Mature HDL
CE=Cholesterol ester, FC=Free cholesterol, HDL=High density lipoprotein,
IDL=Intermediate density lipoprotein, LDL-R=Low density lipoprotein
receptor, LPL=Lipoprotein lipase, TG=Triglyceride,Fibrate Evidence:
Effect on Lipid Parameters
180 patients with type IIa or IIb hyperlipidemia randomized to fenofibrate
(100 mg three times daily) or placebo for 24 weeks
Type IIa hyperlipidemia Type IIb hyperlipidemia
50
Mean % change from baseline
40
30
20 +15*
+11*
10
LDL TG LDL TG
0
HDL HDL
-10 -6*
-20
-20*
-30
-40 -38*
-50 -45*
-60 *pFibrate Evidence:
Primary and Secondary Prevention
30 42%
% CHD Death/Nonfatal MI
Rx 22%
25 22
Placebo 22***
9%
20 17
15
66% 13.6 13
15
34%
10 8
2.7 4.1*** 2.7
5
0 HHS HHS* BIP BIP** VA-HIT
PRIMARY PREVENTION SECONDARY PREVENTION
*Post hoc analysis of subgroup with TG >200 mg/dL and HDL-CFibrate Evidence:
Primary Prevention
Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD)
9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo
for 5 years
11% RRR
9
Nonfatal MI (%)
CHD Death or
5.9
6 5.2
3
P=0.16
0
Placebo Fenofibrate
A fibrate does not provide significant additional benefit* in diabetics
*Unadjusted for concomitant statin use
CHD=Coronary heart disease, MI=Myocardial infarction
Source: Keech A et al. Lancet 2005;366:1849-61Fibrate Evidence:
Primary and Secondary Prevention
Action to Control Cardiovascular Risk in Diabetes
(ACCORD) Lipid Trial
5,518 diabetic patients on statin therapy randomized to fenofibrate
(160 mg) or placebo for 4.7 years
8% RRR
3
CV death, nonfatal
stroke or nonfatal
2.4 2.2
MI (%/year)
2
1
P=0.32
0
Placebo Fenofibrate
On a background of statin therapy, a fibrate does not reduce CV events
in diabetics
CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction
Source: ACCORD study group. NEJM 2010;Epub ahead of printEffect of Pharmacotherapy
on Lipid Parameters
Patient
Therapy TC LDL-C HDL-C TG
tolerability
Statins* - 19-37% - 25-50% + 4-12% - 14-29% Good
Ezetimibe - 13% - 18% + 1% - 9% Good
Bile acid
- 7-10% - 10-18% + 3% Neutral or - Poor
sequestrants
Reasonable
Nicotinic acid - 10-20% - 10-20% + 14-35% - 30-70%
to Poor
Fibrates - 19% - 4-21% + 11-13% - 30% Good
*Daily dose of 40mg of each drug, excluding rosuvastatin
HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein
cholesterol, TC=Total cholesterol, TG=Triglycerides-3 Fatty Acids Evidence:
Effect on Lipid Parameters
27 patients with hypertriglyceridemia and low HDL-C treated with -3 fatty
acid (4 grams/day) for 7 months
Total
Triglyceride Cholesterol
0
-10
% Reduction
-20
-21*
-30
-40
-50 -46*
*P-3 Fatty Acids Evidence:
Primary and Secondary Prevention
Japan Eicosapentaenoic acid Lipid Intervention Study
(JELIS) randomized to EPA (1800 mg)
18,645 patients with hypercholesterolemia
with a statin or a statin alone for 5 years
Years
-3 fatty acids provide CV benefit, particularly in secondary prevention
*Composite of cardiac death, myocardial infarction, angina, PCI, or CABG
Source: Yokoyama M et al. Lancet. 2007;369:1090-8-3 Fatty Acids Evidence:
Secondary Prevention
Diet and Reinfarction Trial (DART)
2,033 men with a history of a MI randomized to a diet of reduced fat with an
increased ratio of polyunsaturated to saturated fat, increased fatty fish
intake*, or increased fiber intake for 2 years
8.0%
All cause mortality (%)
7.0%
6.0%
5.0% N-3 Fatty Acids
4.0% Placebo
3.0%
2.0%
1.0%
0.0%
-3 fatty acids reduce all cause mortality** after a MI
*Corresponds to 2.5 grams of EPA (PUFA)
**p-3 Fatty Acids Evidence:
Secondary Prevention
Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
miocardico (GISSI-Prevenzione)
11,324 patients with a history of a MI randomized to -3 polyunsaturated
fatty acids [PUFA] (1 gram), vitamin E (300 mg), both or none for 3.5 years
P=0.023
Percent of patients
16
P=0.048
14 P=0.053 P=0.008
12
10 N-3 PUFA
8
Placebo
6
4
2
0
Death, CV Death, CV
NF MI, death, NF MI, death,
NF stroke NF MI, NF stroke NF MI,
(2 way) and NF (4 way) and NF
stroke stroke
-3 fatty acids provide significant CV benefit after a MI
CV=Cardiovascular, MI=Myocardial infarction, NF=Non-fatal
Source: GISSI Investigators. Lancet 1999;354:447-455-3 Fatty Acids Evidence:
Secondary Prevention
OMEGA Trial
3,827 patients 3-14 days following a MI randomized to -3 fatty acids (460
mg EPA + 380 mg DHA) or placebo for 1 year
stroke, or death* (%) 12 10.4
Rate of reinfarction,
8.8
8
4
P=0.10
0
Placebo Fatty acids
-3 fatty acids provide no benefit following a MI in those with high
utilization of risk reducing therapies
*This is a secondary endpoint
MI=Myocardial infarction
Source: Senges J et al. Presented at the Annual Scientific Sessions of the
American College of Cardiology, March 2009, Orlando, FLRisk Assessment for
LDL-C Lowering
A risk assessment tool* is needed for individuals with >2 RFs
10-year CHD Risk
0 10 20
0-1 RFs
2 RFs
CAD or Risk
Equivalent**
**Includes DM, non-coronary atherosclerotic vascular disease, and
>20% 10-year CHD risk by the FRS
*Such as the Framingham Risk Score (FRS)
CAD=Coronary artery disease, CHD=Coronary heart disease,
DM=Diabetes mellitus, RF=Risk factor
Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol
in Adults. JAMA 2001;285:2486-97Risk Stratification:
Framingham Risk Score for Men
Step 1: Age Points Step 3: HDL-C Points Step 5: Smoking Status Points
Years Points HDL-C (mg/dl) Points Age Age Age Age Age
20-39 40-49 50-59 60-69 70-79
20-34 -9 >60 -1
Nonsmoker 0 0 0 0 0
35-39 -4 50-59 0 Smoker 8 5 3 1 1
40-44 0 40-49 1
45-49 3Risk Stratification:
Framingham Risk Score for Women
Step 1: Age Points Step 3: HDL-C Points Step 5: Smoking Status Points
Years Points HDL-C (mg/dl) Points Age Age Age Age Age
20-39 40-49 50-59 60-69 70-79
20-34 -7 >60 -1
Nonsmoker 0 0 0 0 0
35-39 -3 50-59 0
Smoker 9 7 4 2 1
40-44 0 40-49 1
45-49 3ATP III LDL-C Goals and
Cut-points for Drug Therapy
Consider
Risk Category LDL-C Goal Initiate TLC Drug Therapy
High risk: 100 mg/dL
CHD or CHD risk equivalents (optional goal: (20%) 55 years in
women
ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-
density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes
Source: Grundy S et al. Circulation 2004;110:227-39ATP III Classification of Other Lipoprotein Levels
Total Cholesterol HDL-Cholesterol
Level (mg/dl) Classification Level (mg/dl) Classification
40 Minimum goal*
200-239 Borderline High 40-50 Desired goal*
>240 High >50 High
Triglyceride
Level (mg/dl) Classification
500 Very High
*These goals apply to men. For women, the minimum goal is >50 mg/dL
Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-97Cholesterol Management Guidelines
Goals Recommendations
As set forth by the Obtain a fasting lipid profile in all patients. For those with
NCEP 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 (Cholesterol Management Guidelines (Continued)
Goals Recommendations
As set forth by the HMG-CoA reductase inhibitors (statins) are used first-line to
NCEP 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 >150 mg/dl or the HDL-C level is 500 mg/dl, nicotinic acid or a fibrate should
be considered before starting LDL-C lowering therapy
HDL-C=High density lipoprotein cholesterol, LDL-C=Low density
lipoprotein cholesterol, TG=Triglyceride
Source: Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults. JAMA 2001;285:2486-97Cholesterol Management Guidelines (Continued)
Secondary Prevention
I IIa IIb III Reduce intake of saturated fat (Cholesterol Management Guidelines (Continued)
Secondary Prevention
I IIa IIb III A fasting lipid profile should be obtained in all
patients within 24 hrs of hospitalization for a
NSTE-ACS
I IIa IIb III In the absence of contraindication, a HMG-CoA
reductase inhibitor should be initiated in all NSTE-
ACS patients, regardless of baseline LDL-C level
and dietary modification
LDL-C=Low density lipoprotein cholesterol, NSTE-ACS=Non ST-Segment
Elevation Acute Coronary Syndrome
Source: Anderson JL et al. JACC 2007;50:652-726Cholesterol Management Guidelines (Continued)
I IIa IIb III 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
I IIa IIb III women) in those with a TG level of 200-499
mg/dl
I IIa IIb III Initiation of a fibrate or niacin before LDL-C
lowering drug therapy in those with a TG level
>500 mg/dl
LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride
Source: Smith SC Jr. et al. JACC 2006;47:2130-9Cholesterol Management Guidelines (Continued)
Secondary Prevention
I IIa IIb III Initiation or intensification of LDL-C lowering drug
therapy to achieve a LDL-C goalCholesterol Management Guidelines (Continued)
Secondary Prevention
I IIa IIb III
Intensification of LDL-C lowering drug
therapy (Class I, Level B) or addition of a
I IIa IIb III fibrate or niacin (Class IIa, Level B) to
reduce non-HDL-C
I IIa IIb III Initiation of a fibrate or niacin before LDL-C
lowering drug therapy in those with a TG
level >500 mg/dl to achieve a non-HDL-
cholesterolCholesterol Management Guidelines (Continued)
Secondary Prevention
I IIa IIb III Reduction of non-HDL-cholesterol toYou can also read
