The Evidence for Current Cardiovascular
Disease Prevention Guidelines:
Cholesterol Management
Evidence and Guidelines
American College of Cardiology
Best Practice Quality Initiative Subcommittee
and Prevention Committee
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,
VLDL, and
their catabolic remnants
LDL
HDL
> 30 nm
20–22 nm
9–15 nm
Potentially
pro-inflammatory
Potentially
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
LDL
Endothelial
injury
LDL
+
VLDL
LDL infiltration
into intima
Adherence
of platelets
Oxidative
modification
of LDL
+
Macrophages
Release
of PDGF
Liver
Cholesterol
excreted
LCAT
APO-A1
Foam cells
Fatty streak
Other
growth
factors
Advanced
fibrocalcific
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 lipoprotein
Attributable Risk Factors
for a First Myocardial Infarction
INTERHEART Study
100
90
PAR (%)
80
60
40
50
36
20
0
33
14
Smoking
12
Fruits/ Exercise
Veg
18
7
Alcohol
Hypertension
20
10
Diabetes Abdominal Psychoobesity
social
Lipids
All 9 risk
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;364:937-952
Change in Total Cholesterol Levels
in the United States Over Time
National Health and Nutrition Examination Survey (NHANES)
Total Cholesterol mg/dl (mmol/L)
age-adjusted percentage
100%
90%
80%
70%
60%
50%
40%
>240 mg/dL (>6.21 mmol/L)
200-240 mg/dL (5.17-6.21 mmol/L)
30%
<200 mg/dL (<5.17 mmol/L)
20%
10%
0%
Source: Ford ES et al. Circulation 2009;120:1181-1188
Coronary Heart Disease Risk According to
LDL-C Level
Relative Risk for Coronary
Heart Disease (Log Scale)
3.7
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;110:227-239
Therapies to Lower Levels of LDL-C
Class
3-Hydroxy-3-Methylglutaryl Coenzyme A (HMGCoA) reductase inhibitors [Statins]
Bile acid sequestrants
Cholesterol absorption inhibitor
Nicotinic acid
Dietary Adjuncts
Drug(s)
Atorvastatin (Lipitor)
Fluvastatin (Lescol XL)
Lovastatin (Mevacor)
Pitavastatin (Livalo)
Pravastatin (Pravachol)
Rosuvastatin (Crestor)
Simvastatin (Zocor)
Cholestyramine (Questran)
Colesevelam (Welchol)
Colestipol (Colestid)
Ezetimibe (Zetia)
Niacin
Soluble fiber
Soy protein
Stanol esters
HMG-CoA Reductase Inhibitor:
Mechanism of Action
Inhibition of the cholesterol biosynthetic pathway
Squalene
synthase
HMG-CoA
Reductase
Acetyl
CoA
HMGCoA
Mevalonate
Farnesyl
pyrophosphate
Dolichol
Squalene
Cholesterol
Farnesyltransferase
E,E,E-Geranylgeranyl
pyrophosphate
Farnesylated
proteins
Geranylgeranylated
proteins
Ubiquinones
HMG-CoA Reductase Inhibitor:
Mechanism of Action
VLDL
Cholesterol
synthesis
LDL receptor
(B–E receptor)
synthesis
Intracellular
Cholesterol
VLDLR
Apo B
Apo E
LDL-R–mediated hepatic
uptake of LDL and VLDL
remnants
Serum LDL-C
LDL
Apo B
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
HDL=High density lipoprotein, LDL=Low density lipoprotein
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
Pravastatin 20/40*
27
12
6
35
Simvastatin 20/80*
Fluvastatin 20/80*
19
12
12
37
Atorvastatin 10/80*
Rosuvastatin 10/20†
18
46
Pitavastatin 1/4‡
6
32
0
10
11
20
30
40
50
60
Each doubling of the statin dose produces an approximate 6%
reduction in the LDL-C level
Sources:
*Illingworth DR. Med Clin North Am 2000;84-23-42
†Crestor Package Insert. http://www1.astrazeneca-us.com/pi/crestor.pdf
‡Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf
HMG-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)
*Standardized to LDL-C 186 mg/dL (mean concentration in trials)
before Rx.† Independent of pre-Rx LDL-C
‡Maximum dose of 80 mg/day administered as two 40-mg tablets
§Not FDA approved at 80 mg/day
#Data presented as absolute reductions in LDL-C* (mg/dL)
and percent reductions in LDL-C (in parentheses)
‡Although not included in this analysis, pitavastatin would be
expected to achieve a 32%, 36%, and 43% mean reduction in
LDL-C levels at the 1 mg, 2 mg, and 4 mg daily doses, respectively
FDA=Food and Drug Administration, LDL-C=Low
density lipoprotein cholesterol, Rx=Treatment
Sources:
Law
MR et al. BMJ 2003;326:1423-1427
Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf
HMG-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
2010
SEARCH
HMG-CoA Reductase Inhibitor Evidence:
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
31% RRR
Rate of MI or CHD
death (%)
9
7.5
6
5.3
3
0
P<0.001
Placebo
Pravastatin
A statin provides significant benefit in those with average cholesterol levels
CHD=Coronary heart disease, MI=Myocardial
infarction, RRR=Relative risk reduction
Source: Shepherd J et al. NEJM 1995;333:1301-1307
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
West of Scotland Coronary Prevention Study (WOSCOPS)
Long-term follow-up at 5 and 10 years after conclusion of the study
Risk of MI or CHD
death (%)
RRR=27%, p<0.001
RRR=18%, p<0.02
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;357:1477-1486
HMG-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 (2040 mg) or placebo for 5 years
Rate of MI, unstable
angina, or SCD (%)
37% RRR
6
5.5
4
3.5
2
0
P<0.001
Placebo
Lovastatin
A statin provides benefit in those with average LDL-C levels
LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction,
RRR=Relative risk reduction, SCD=Sudden cardiac death
Source: Downs JR et al. JAMA 1998;279:1615–1622
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial—Lipid Lowering Arm (ALLHAT-LLA)
Cumulative rate %
10,355 patients with HTN and >1 CHD risk factor randomized to
pravastatin (40 mg) or usual care for 5 years
18
Pravastatin
Usual care
15
12
9
6
32% cross-over
among patients
with CHD
3
RR, 0.99; P=0.88
0
1
2
3
Years
4
5
6
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;288:2998-3007
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering
Arm (ASCOT-LLA)
Cumulative incidence of
MI and fatal CHD (%)
10,305 patients with HTN randomized to atorvastatin (10 mg) or
placebo for 5 years
4
3
Atorvastatin 90 mg/dl*
Placebo
126 mg/dl*
36% RRR
2
1
P=0.0005
0
0.0
0.5
1.0
1.5
2.0
Follow-up (yr)
2.5
3.0
3.5
A statin provides significant benefit in moderate- to high-risk
individuals by lowering LDL-C levels below current goals
*Post-treatment LDL-C level
CHD=Coronary heart disease, HTN=Hypertension, LDL-C=Low
density lipoprotein cholesterol, RRR=Relative risk reduction
Source: Sever PS et al. Lancet. 2003;361:1149-1158
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Relationship between LDL-C levels and event rates in select primary
prevention statin trials
CHD event rate (%)
10
Statin
8
Placebo
WOSCOPS
WOSCOPS
6
AFCAPS
AFCAPS
4
ASCOT
2
ASCOT
0
–1
P=0.0019
55
75
95
115
135
155
175
195
LDL cholesterol (mg/dL)
AFCAPS= Air Force/Texas Coronary Atherosclerosis Prevention Study, ASCOT= AngloScandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, LDL-C=Low density
lipoprotein cholesterol, WOSCOPS= West of Scotland Coronary Prevention Study
Source: O’Keefe JH Jr et al. JACC 2004;43:2142-2146
HMG-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
Number of adverse
CV events* per 1000
person years
33% RRR
6
5.0
4
3.3
2
0
P=0.01
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
CV=Cardiovascular
Source: Nakamura H et al. Lancet 2006;368:1155-63
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Justification for the Use of Statins in Prevention: An
Intervention Trial Evaluating Rosuvastatin (JUPITER)
Cumulative incidence of CV
death, MI, stroke,
hospitalization
for unstable angina, and
arterial revascularization
0.00
0.04
0.08
17,802 men (>50 years) and women (>60 years) with LDL-C <130 mg/dL
and hs-CRP >2 mg/L randomized to rosuvastatin (20 mg) or placebo for up
to 5 years*
Rosuvastatin
Placebo
44% RRR
P<0.00001, NNT=25
0
1
2
Follow-up (years)
3
4
A statin provides benefit in those with elevated hs-CRP levels
*The study was stopped prematurely after 1.9 years
CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction
Ridker PM et al. NEJM 2008;359:2195-2207
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Myocardial Ischemia Reduction with Aggressive Cholesterol
Lowering (MIRACL) Trial
event
15
15
Combined CV
rate (%)*
3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo
for 16 weeks
10
10
17.4%
Placebo
14.8%
Atorvastatin
55
0
0
RR=0.84, P=0.048
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.
ACS=Acute coronary syndrome, CV=Caradiovascular
Source: Schwartz GG et al. JAMA 2001;285:1711-1718
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Pravastatin or Atorvastatin Evaluation and Infection Therapy
(PROVE-IT)—TIMI 22 Study
Recurrent MI, cardiac death,
UA, revascularization, or stroke
4,162 pts with an ACS randomized to atorvastatin (80 mg) or pravastatin
(40 mg) for 24 months
30
16% RRR
Pravastatin
25
Atorvastatin
20
15
10
5
0
P=0.005
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, RRR=Relative risk reduction, UA=Unstable angina
Source: Cannon CP et al. NEJM 2004;350:1495-1504
HMG-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
Cumulative event
rate (%)*
20
Placebo/Simvastatin 20 mg/day
15
Simvastatin 40/80 mg/day
10
5
HR=0.89, P=0.14
0
0
4
8
12
16
Time from randomization (months)
20
24
Acute intensive statin therapy does not provide CV benefit
*Includes CV death, MI, readmission for an ACS, and CVA
ACS=Acute coronary syndrome, CV=Cardiovascular,
CVA=Cerebrovascular accident, MI=Myocardial infarction
Source: de Lemos JA et al. JAMA 2004;292:1307-1316
HMG-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
Mortality (%)
12
11.5
8.2
8
4
0
P<0.001
Placebo
Simvastatin
A statin provides significant benefit in those with average LDL-C levels
LDL-C=Low density lipoprotein cholesterol,
MI=Myocardial infarction, RRR=Relative risk reduction
Source: 4S Group. Lancet 1994;344:1383–1389
HMG-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
Rate of MI or CHD
death (%)
24% RRR
15
13.2
10.2
10
5
0
P=0.003
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;335:1001–1009
HMG-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
CHD Death (%)
9
8.3
6.4
6
3
0
P<0.001
Placebo
Pravastatin
A statin provides significant benefit across a broad range of cholesterol levels
CHD=Coronary heart disease, MI=Myocardial
infarction, RRR=Relative risk reduction
Source: LIPID Study Group. NEJM 1998;339:1349–1357
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Heart Protection Study (HPS)
Event Rate Ratio (95% CI)
Baseline
LDL-C (mg/dL)
Statin
(n = 10,269)
Placebo
(n = 10,267)
<100
282 (16.4%)
358 (21.0%)
100–129
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 (0.72–0.81)
P<0.0001
0.4
0.6
0.8
1.0
1.2
1.4
A statin provides significant CV benefit regardless of baseline LDL-C level
CAD=Coronary artery disease, CI=Confidence interval,
CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol
Source: HPS Collaborative Group. Lancet 2002;360:7-22
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)
CHD death, non-fatal
MI, stroke (%)
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
20
Placebo
10
Pravastatin
15% RRR, P=0.014
0
0
1
2
Years
3
4
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;360:1623-1630
HMG-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
Major CV Event* (%)
0.15
22% RRR
Atorvastatin (10 mg)
0.10
Atorvastatin (80 mg)
0.05
P<0.001
0.00
0
1
2
3
Years
4
5
6
High-dose statin therapy provides benefit in chronic CHD
*Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke
CHD=Coronary heart disease, CV=Cardiovascular,
MI=Myocardial infarction, RRR=Relative risk reduction
Source: LaRosa JC et al. NEJM 2005;352:1425-35
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Incremental Decrease in End Points Through Aggressive Lipid
Lowering (IDEAL) Trial
Cumulative Hazard (%)
8,888 patients with a history of acute MI randomized to atorvastatin (80 mg) or
simvastatin (20 mg) for 5 years
12
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 does not provide CV benefit after a MI
*Includes coronary death, hospitalization for nonfatal
acute MI, or cardiac arrest with resuscitation
CV=Cardiovascular, HR=Hazard ratio, MI=Myocardial infarction
Source: Pedersen TR et al. JAMA 2005;294:2437-2445
HMG-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
4S
Statin
Placebo
Event (%)
25
4S
20
LIPID
CARE
CARE
HPS
HPS
TNT (atorvastatin 10 mg/d)
TNT (atorvastatin 80 mg/d)
LIPID
15
10
5
0
0
70
90
110
130
150
LDL-C (mg/dL)
170
190
210
CARE=Cholesterol and Recurrent Events Trial, CHD=Coronary heart
disease, HPS=Heart Protection Study, LDL-C=Low density lipoprotein
cholesterol, LIPID=Long-term Intervention with Pravastatin in Ischaemic
Disease, 4S=Simvastatin Survival Study, TNT=Treating to New Targets
Source: LaRosa JC et al. NEJM 2005;352:1425-1435
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Study of the Effectiveness of Additional Reductions in
Cholesterol and Homocysteine (SEARCH)
12,064 patients with a history of MI randomized to simvastatin (80 mg) or
simvastatin (20 mg) for a mean of 6.7 years
*
High-dose statin therapy does not provide CV benefit after a MI
*Includes coronary death, myocardial
infarction, stroke, or arterial revascularization
CHD=Coronary heart disease, MI=Myocardial infarction
Source: SEARCH Collaborative Group. Lancet 2010;376:1658-1669
HMG-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
Risk Reduction
Absolute
Risk Reduction
Number Needed
To Treat
Primary
Secondary
Primary
Secondary
Primary
Secondary
Major CHD
events
29.2
20.8
1.66
2.4
60
33
Major CV
events
14.4
17.8
0.37
0.8
268
125
Nonfatal
MI
31.7
NA
1.65
NA
61
NA
PCI or
CABG
33.8
20.3
1.08
2.7
93
37
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;166:2307-2313
HMG-CoA Reductase Inhibitor Evidence:
Effect of Intensive Therapy
Magnitude of event reduction among trials of intensive statin therapy
Trial
Population
Duration
(years)
LDL-C Reduction
(mg/dL)
RR in Primary
End Point (%)
RR in MI or CHD
Death (%)
PROVE ITTIMI 22
ACS
(N = 4162)
2
33
16
16
A to Z
ACS
(N = 4497)
2
14
11
15
TNT
Stable CAD
(N =10,001)
5
24
22
21
IDEAL
Stable CAD
(N = 8888)
5
23
11
11
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;294:2492-2494
HMG-CoA Reductase Inhibitor Evidence:
Effect of Intensive Therapy
Cholesterol Treatment Trialists’ (CTT) Collaboration
Control
15
Statin
21% relative risk
reduction per mmol/L
16% relative risk
reduction per 0.5 mmol/L
10
More statin
0
Five year risk of a major
vascular event, %
20
Meta-analysis of 169,138 patients randomized to at least
2 years of statin therapy
0
1
2
3
4
5
LDL cholesterol level (mmol/L)
There is a proportionate reduction in CV events with greater
cholesterol reduction
LDL-
CV=Cardiovascular, LDL=Low density lipoprotein
Source: Cholesterol Treatment Trialists’ Collaboration. Lancet 2010;376:1670-1681
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
Source: Kashani A et al. Circulation 2006;114:2788-2797
HMG-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)
*General term to describe diseases of muscles
**Itraconazole, Ketoconazole
†Erythromycin, Clarithromycin
‡Chronic renal insufficiency, especially from
diabetes mellitus
Source: Pasternak RC et al. Circulation 2002;106:1024-1028
Bile Acid Sequestrant:
Mechanism of Action
Gall Bladder
 Cholesterol 7- hydroxylase
 Conversion of cholesterol to BA
 BA Secretion
Bile Acid
Enterohepatic Circulation
Liver
Terminal Ileum
 BA Excretion
Reabsorption of
bile acids
 LDL Receptors
 VLDL and LDL removal
 LDL-C
BA=Bile acid, LDL-C=Low density lipoprotein cholesterol,
VLDL=Very low density lipoprotein
Bile Acid Sequestrant Evidence:
Efficacy at Reducing LDL-C
15
LDL-C
HDL-C
TG
10
% Change from baseline
at week 24
10
5
0
3
†
5
0
-1
-5
-10
Placebo
-15
Colesevelam 3.8 grams/day
-15 *
-20
*P<0.001 vs placebo
†P=0.04 vs placebo
HDL-C=High density lipoprotein cholesterol, LDL-C=Low
density lipoprotein cholesterol, TG=Triglyceride
Source: Insull W et al. Mayo Clin Proc 2001;76:971-982
Bile 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
Rate of MI or CHD
death (%)
9
8.6
7.0
6
3
0
P<0.05
Placebo
Cholestyramine
A bile acid sequestrant provides benefit in those with high cholesterol levels
CHD=Coronary heart disease, MI=Myocardial
infarction, RRR=Relative risk reduction
Source: The LRC-CPPT Investigators. JAMA 1984;251:351-364
Ezetimibe:
Mechanism of Action
Production in liver
Absorption from intestine
Bloodstream
Dietary cholesterol
LDL-C
Cholesterol
synthesis
VLDL
Biliary cholesterol
Chylomicrons
Fecal sterols and neutral sterols
Ezetimibe 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
Mean % change from
baseline to week 12
+5
0
+1.3
+0.4
–1.6
–5
–5.7
–10
Placebo
–15
–16.9*
Ezetimibe 10 mg
–20
*p<0.01 compared to placebo
HDL-C=High density lipoprotein cholesterol,
LDL-C=Low density lipoprotein cholesterol
Source: Dujovne CA et al. Am J Cardiol 2002;90:1092-1097
Dietary 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%
LDL-C=Low density lipoprotein cholesterol
Sources:
Kwiterovich Jr PO. Pediatrics 1995;96:1005-1009
Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214
Miettinen TA et al. Ann Med 2004;36:126-134
CHD Risk According to HDL-C Level
Framingham Study
CHD risk ratio
4.0
4.0
3.0
2.0
2.0
1.0
1.0
0
65
25
45
HDL-C (mg/dL)
CHD=Coronary heart disease, HDLC=High-density lipoprotein cholesterol
Source: Kannel WB. Am J Cardiol 1983;52:9B–12B
Nicotinic Acid:
Mechanism of Action
Mobilization of FFA
TG
synthesis
Apo B
Apo B
VLDL
VLDL
Serum LDL
VLDL
secretion
LDL
Hepatocyte
Serum VLDL
results in reduced
lipolysis to LDL
HDL
Systemic Circulation
Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in
reduced LDL cholesterol levels and increased HDL cholesterol levels
FFA=Free fatty acid, 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=14
Nicotinic Acid Evidence:
Effect on Lipid Parameters
30%
30
22%
Mean change from Baseline
HDL-C
15%
20
10
26%
30%
10%
0
–9%
-10
-20
–14%
–5%
–17%
–22%
–11%
-30
–21%
LDL-C
–28%
-40
–35%
-50
Triglyceride
–39%
–44%
Dose (mg)
500
1000
1500
2000
2500
3000
HDL-C=High density lipoprotein cholesterol, LDL-C=Low
density lipoprotein cholesterol, TG=Triglyceride
Source: Goldberg A et al. Am J Cardiol 2000;85:1100-1105
Nicotinic Acid Evidence:
Secondary Prevention
Coronary Drug Project (CDP)
Survival (%)
8,341 men with previous myocardial infarction randomized to nicotinic
acid (3 grams) or placebo for 15 years
100
90
80
70
60
5
0
40
Nicotinic Acid
Nicotinic acid
stopped
Placebo
P=0.0012
0
2
4
6
8
10
12
14
16
Years of follow-up
Niacin provides long-term benefit following a MI
MI=Myocardial infarction
Source: Canner PL et al. JACC 1986;8:1245–1255
Nicotinic Acid Evidence:
Secondary Prevention
HDL-Atherosclerosis Treatment Study (HATS)
160 men with CAD, low HDL-C, and normal LDL-C randomized to simvastatin (1020 mg) + niacin (1000 mg bid), simvastatin (10-20 mg) + niacin (1000 mg bid) +
antioxidants, antioxidants, or placebo for 3 years
*
**
**
Placebo (n=34)
Niacin/Simvastatin (n=33)
Placebo + Vitamins (n=39)
Niacin/Simvastatin + Vitamins (n=40)
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
**p<0.01, but low absolute event rates
CAD=Coronary artery disease, HDL-C=High density lipoprotein
cholesterol, LDL-C=Low density lipoprotein cholesterol
Source: Brown BG et al. NEJM 2001;345:1583-1592
Nicotinic Acid Evidence:
Secondary Prevention
Atherothrombosis Intervention in Metabolic Syndrome with
Low HDL/High Triglycerides: Impact of Global Health
Outcomes (AIM-HIGH) Trial
Primary outcome (%)**
3414 patients with established CV disease randomized to niacin (up to 2000
mg/day) or placebo on a background of statin therapy for a mean of 3 years*
16.4%
20
Combination Therapy
Monotherapy
16.2%
10
HR 1.02, p=0.79
0
0
1
2
3
4
Time (years)
Niacin provides no benefit to those with CV disease and low HDL-C levels
*The study was stopped prematurely
**Composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for
ACS, or symptom-driven coronary/cerebral revascularization
CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol
Source: AIM-HIGH Investigators. NEJM 2011;365:2255-2267
Nicotinic Acid Evidence:
Secondary Prevention
Heart Protection Study 2-Treatment of HDL to Reduce the
Incidence of Vascular Events (HPS2-THRIVE) Trial
Major vascular events (%)
25,673 patients with established CV disease randomized to extended release
niacin (up to 2000 mg/day) plus laropiprant (40 mg/day) or placebo on a
background of statin therapy for a median of 3.9 years*
15.0%
14.5%
15
Placebo
Niacin/Laropiprant
10
5
HR 0.96, p=0.29
0
0
1
2
3
4
Years of follow-up
Niacin provides no benefit to those with CV disease and low HDL-C levels
*The study was stopped prematurely
CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol
Source: Armitage J et al. Presented at Late Breaking Clinical
Trials Session, ACC13, www.thrivestudy.org
Cholesterol Ester Transfer Protein Evidence:
Mechanism of Action
LDL-R
Liver
F
C
SR-B1
CE
CETP
Vessel
Wall
LDL/VL
DL
CE
Bile
LCAT
FC
Free Cholesterol in
Extrahepatic tissues
HDL
Inhibition of CETP limits the transfer of cholesterol esters from HDL particles to
triglyceride-rich lipoproteins and results in elevated HDL cholesterol levels along with
larger and less dense LDL cholesterol particles
CE=Cholesterol ester, CETP=Cholesterol ester transfer protein, FC=Free
cholesterol HDL=High density lipoprotein, LCAT=Lecithin carnitine acyl
transferase, LDL=Low density lipoprotein, VLDL=Very low density lipoprotein
Cholesterol Ester Transfer Protein Evidence:
Secondary Prevention
Investigation of Lipid Level Management to Understand its
Impact in Atherosclerotic Events (ILLUMINATE) Trial
P=0.001
9
6
3
6.2
5.0
3
0
Atorvastatin
Atorvastatin and
Torcetrapib
All-cause
mortality (%)
Primary end point** (%)
15,067 patients at high CV risk randomized to torcetrapib (60 mg/day) plus
atorvastatin versus atorvastation alone for a median of 1.5 years*
P=0.006
2
1.2
1
0
0.8
Atorvastatin
Atorvastatin and
Torcetrapib
The CETP inhibitor, torcetrapib, is associated with increased CV risk
*The trial was stopped prematurely
**Composite of death from coronary heart disease, nonfatal
myocardial infarction, stroke, or hospitalization for unstable angina
CETP=Cholesterol ester transfer protein, CV=Cardiovascular
Source: Barter PJ et al. NEJM 2007;357:2109-2122
Cholesterol Ester Transfer Protein Evidence:
Secondary Prevention
Dal-OUTCOMES Trial
15,871 patients with a recent ACS randomized to dalcetrapib (600 mg/day)
or placebo for a median of 2.6 years
Primary end point** (%)
P=0.52
9
8.3
8.0
6
3
0
Placebo
Dalcetrapib
The CETP inhibitor, dalcetrapib, is associated with no CV benefit
*The trial was stopped prematurely
**Composite of death from coronary heart disease, nonfatal myocardial
infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation
ACS=Acute coronary syndrome, CETP=Cholesterol
ester transfer protein, CV=Cardiovascular
Source: Barter PJ et al. NEJM 2007;357:2109-2122
CHD 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;115:450-458
Fibrate:
Mechanism of Action
TG
VLDL
LPL
+
Fibrate
+
Intestine
IDL
LDL-R
Liver
CE
Mature HDL
FC
Nascent
HDL
FC
CE
Macrophage
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, VLDL=Very low density lipoprotein
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
50
Type IIa hyperlipidemia
Type IIb hyperlipidemia
Mean % change from baseline
40
30
20
10
0
+11*
LDL
-30
-40
-50
TG
HDL
-10
-20
+15*
LDL
-6*
TG
HDL
-20*
-38*
-45*
*p<0.01
HDL=High density lipoprotein, LDL=Low
density lipoprotein, TG=Triglyceride
Source: Knopp RH et al. Am J Med 1987;83:50-9
% CHD Death/Nonfatal MI
Fibrate Evidence:
Primary and Secondary Prevention
42%
Treatment arm
22%
22
Placebo
22***
9%
17
66%
34%
2.7
4.1***
13.6
15
13
8
2.7
HHS
HHS*
Primary Prevention
Secondary Prevention
*Post hoc analysis of subgroup with TG >200 mg/dL and HDL-C <42 mg/dL
**Post hoc analysis of subgroup with TG 200 mg/dL and HDL-C <35 mg/dL
***Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05)
HDL-C=High density lipoprotein cholesterol, TG=Triglyceride
Sources:
Frick MH et al. NEJM 1987;317:1237-1245
Manninen V et al. Circulation 1992;85:37-45
BIP Study Group. Circulation 2000;102:21-27
Rubins HB et al. NEJM 1999;341:410-418
Fibrate 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
CHD Death or
Nonfatal MI (%)
9
6
5.9
5.2
3
0
P=0.16
Placebo
Fenofibrate
A fibrate does not provide significant additional benefit* in diabetics
*Unadjusted for concomitant statin use
CHD=Coronary heart disease, MI=Myocardial
infarction, RRR=Relative risk reduction
Source: Keech A et al. Lancet 2005;366:1849-1861
Fibrate 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
CV death, nonfatal
stroke or nonfatal
MI (%/year)
8% RRR
3
2.4
2.2
2
1
0
P=0.32
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;362:1563-1574
Effect of Pharmacotherapy
on Lipid Parameters
TC
LDL-C
HDL-C
TG
Patient
tolerability
- 19-37%
- 25-50%
+ 4-12%
- 14-29%
Good
- 13%
- 18%
+ 1%
- 9%
Good
Bile acid
sequestrants
- 7-10%
- 10-18%
+ 3%
Neutral or
Poor
Nicotinic acid
- 10-20%
- 10-20%
+ 14-35%
- 30-70%
Reasonable
to Poor
- 19%
- 4-21%
+ 11-13%
- 30%
Good
Therapy
Statins*
Ezetimibe
Fibrates
*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=Triglyceride
Omega-3 Fatty Acids Evidence:
Effect on Lipid Parameters
27 patients with hypertriglyceridemia and low HDL-C treated with omega-3
fatty acid (4 grams/day) for 7 months
Triglyceride
0
Total
Cholesterol
% Reduction
-10
-20
-21*
-30
-40
-50
-46*
*P<0.05
HDL-C=High-density lipoprotein cholesterol
Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731
Omega-3 Fatty Acids Evidence:
Primary and Secondary Prevention
Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS)
18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a
statin or a statin alone for 5 years
Years
Omega-3 fatty acids provide CV benefit, particularly in secondary prevention
*Composite of cardiac death, myocardial infarction, angina, PCI, or CABG
CV=Cardiovascular, EPA=Eicosapentaenoic acid
Source: Yokoyama M et al. Lancet 2007;369:1090-1098
Omega-3 Fatty Acids Evidence:
Primary and Secondary Prevention
Outcome Reduction with Initial Glargine Intervention (ORIGIN)
12,536 patients with IFG, IGT, DM, established CV disease, or CV risk factors
randomized in 2 x 2 trial design to omega 3 fatty acids (at least 900 mg/day),
insulin glargine (with a target fasting blood glucose <95 mg/dL) or placebo for a
median of 6.2 years
2% RRR
CV death (%)
15
10
9.3
9.1
5
0
P=0.72
Placebo
Omega 3
fatty acids
Low dose omega-3 fatty acids do not provide CV benefit in at risk individuals
CV=Cardiovascular, DM=Diabetes mellitus,
IFG=Impaired fasting glucose, IGT=Impaired glucose
tolerance
Source: ORIGIN Trial Investigators. NEJM 2012;367:309-318
Omega-3 Fatty Acids Evidence:
Secondary Prevention
Diet and Reinfarction Trial (DART)
All cause mortality (%)
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%
7.0%
6.0%
5.0%
4.0%
3.0%
Omega-3
Fatty Acids
Placebo
2.0%
1.0%
0.0%
Omega-3 fatty acids reduce all cause mortality** in men after a MI
*Corresponds to 2.5 grams of EPA (PUFA)
**p<0.05
EPA=Eicosapentaenoic acid, MI=Myocardial infarction
Source: Burr ML et al. Lancet 1989;2:757-761
Omega-3 Fatty Acids Evidence:
Secondary Prevention
Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
miocardico (GISSI-Prevenzione)
Percent of patients
11,324 patients with a history of a MI randomized to omega-3 polyunsaturated
fatty acids [PUFA] (1 gram), vitamin E (300 mg), both or none for 3.5 years
16
14
12
10
8
6
4
2
0
P=0.048
P=0.053
P=0.023
P=0.008
Omega-3 PUFA
Placebo
Death,
NF MI,
NF stroke
(2 way)
CV
death,
NF MI,
and NF
stroke
Death,
NF MI,
NF stroke
(4 way)
CV
death,
NF MI,
and NF
stroke
Omega-3 fatty acids provide significant CV benefit after a MI
CV=Cardiovascular, MI=Myocardial infarction,
NF=Non-fatal, PUFA=Polyunsaturated fatty acids
Source: GISSI Investigators. Lancet 1999;354:447-455
Omega-3 Fatty Acids Evidence:
Secondary Prevention
OMEGA Trial
Rate of reinfarction,
stroke, or death* (%)
3,827 patients 3-14 days following a MI randomized to omega-3 fatty acids
(460 mg EPA + 380 mg DHA) or placebo for 1 year
12
10.4
8.8
8
4
0
P=0.10
Placebo
Fatty acids
Omega-3 fatty acids provide no benefit following a MI in those with high
utilization of risk reducing therapies
*This is a secondary endpoint
DHA=Docosahexaenoic acid,
EPA=Eicosapentaenoic acid,
MI=Myocardial infarction
Source: Rauch B et al. Circulation 2010;122:2152-2159
Risk 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**
*Such as the Framingham Risk Score (FRS)
**Includes DM, non-coronary atherosclerotic vascular disease, and
>20% 10-year CHD risk by the 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;285:2486-2497
Risk Stratification:
Framingham Risk Score On Line Calculator
Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol
in Adults Risk Assessment Tool. http://hp2010.nhlbihin.net/atpiii/calculator.asp
Risk Stratification:
Framingham Risk Score for Men
Step 1: Age Points
Years
20-34
35-39
Points
-9
-4
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
0
3
6
8
10
11
12
13
Step 3: HDL-C Points
HDL-C (mg/dl)
>60
Points
-1
50-59
40-49
<40
0
1
2
Age
20-39
0
4
7
9
11
Nonsmoker
Smoker
SBP (mm
Hg)
<120
120-129
130-139
140-159
>160
If
untreated
0
0
1
1
2
If
treated
0
1
2
2
3
Age
40-49
0
3
5
6
8
Age
50-59
0
2
3
4
5
Age
60-69
0
1
1
2
3
Age
70-79
0
0
0
1
1
Age
20-39
0
8
Age
40-49
0
5
Age
50-59
0
3
Age
60-69
0
1
Age
70-79
0
1
Step 6: Sum of Points
Age
Total Cholesterol
HDL-C
Systolic Blood Pressure
Step 4: SBP Points
Step 2: Total Cholesterol Points
TC
(mg/dl)
<160
160-199
200-239
240-279
>280
Step 5: Smoking Status Points
Smoking Status
Point Total
Step 7: 10-year CHD Risk
Point
Total
<0
0
1
2
3
4
5
10-year
Risk
<1%
1%
1%
1%
1%
1%
2%
Point
Total
6
7
8
9
10
11
12
10-year
Risk
2%
3%
4%
5%
6%
8%
10%
Point
Total
13
14
15
16
>17
10-year
Risk
12%
16%
20%
25%
>30%
CHD=Coronary heart disease, HDL-C=High density lipoprotein cholesterol,
SBP=Systolic blood pressure, TC=Total cholesterol
Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at
http://www.framinghamheartstudy.org/risk/hrdcoronary.html.
Risk Stratification:
Framingham Risk Score for Women
Step 1: Age Points
Years
20-34
35-39
Points
-7
-3
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
0
3
6
8
10
12
14
16
HDL-C (mg/dl)
>60
50-59
40-49
<40
Points
-1
0
1
2
Age
20-39
0
4
8
11
13
Nonsmoker
Smoker
SBP
(mmHg)
<120
120-129
130-139
140-159
>160
If
untreated
0
1
2
3
4
If
treated
0
3
4
5
6
Age
40-49
0
3
6
8
10
Age
50-59
0
2
4
5
7
Age
60-69
0
1
2
3
4
Age
70-79
0
1
1
2
2
Age
20-39
0
9
Age
40-49
0
7
Age
50-59
0
4
Age
60-69
0
2
Age
70-79
0
1
Step 6: Sum of Points
Age
Total Cholesterol
HDL-C
Systolic Blood Pressure
Step 4: SBP Points
Step 2: Total Cholesterol Points
TC
(mg/dl)
<160
160-199
200-239
240-279
>280
Step 5: Smoking Status Points
Step 3: HDL-C Points
Smoking Status
Point Total
Step 7: 10-year CHD Risk
Point
Total
<9
9
10
11
12
13
14
10-year
Risk
<1%
1%
1%
1%
1%
2%
2%
Point
Total
15
16
17
18
19
20
21
10-year
Risk
3%
4%
5%
6%
8%
11%
14%
Point
Total
22
23
24
>25
10-year
Risk
17%
22%
27%
>30%
CHD=Coronary heart disease, HDL-C=High density lipoprotein cholesterol,
SBP=Systolic blood pressure, TC=Total cholesterol
Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at
http://www.framinghamheartstudy.org/risk/hrdcoronary.html.
Risk Stratification:
Reynolds Risk Score On Line Calculator
In addition to information collected as part of the Framingham Risk Score,
the Reynolds Risk Score includes a hs-CRP level and a family history of
premature CV disease in predicting one’s risk of adverse CV events
Source: Reynolds Risk Score calculator.
http://www.reynoldsriskscore.org/default.aspx
ATP III LDL-C Goals and
Cut-points for Drug Therapy
Risk Category
Consider
Drug Therapy
LDL-C Goal
Initiate TLC
High risk:
CHD or CHD risk equivalents
(10-year risk >20%)
<100 mg/dL
(optional goal:
<70)
100 mg/dL
>100 mg/dL
(<100 mg/dL: consider
drug options)
Moderately high risk:
2+ risk factors*
(10-year risk 10% to 20%)
<130 mg/dL
(optional goal:
<100)
130 mg/dL
>130 mg/dL
(100-129 mg/dL: consider
drug options)
Moderate risk:
2+ risk factors*
(10 year risk <10%)
<130 mg/dL
130 mg/dL
>160 mg/dL
Lower risk:
0-1 risk factor*
<160 mg/dL
160 mg/dL
>190 mg/dL
(160-189 mg/dL: LDL-C
lowering drug optional)
*Risk factors for CHD include: cigarette smoking, hypertension (blood pressure >140/90
mmHg or on antihypertensive medication, HDL-C <40 mg/dl (>60 mg/dl is a negative risk
factor), family history of premature CHD, age >45 years in men or >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;110:227-239
ATP III Classification of Other Lipoprotein Levels
Total Cholesterol
Level (mg/dl)
Classification
HDL-Cholesterol
Level (mg/dl)
Classification
<200
Desirable
>40
Minimum goal*
200-239
Borderline High
40-50
Desired goal*
>240
High
>50
High
Triglyceride
Level (mg/dl)
Classification
<150
Normal
150-199
Borderline High
200-499
High
>500
Very High
*These goals apply to men. For women, the minimum goal is >50 mg/dL
HDL=High density lipoprotein
Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-2497
AHA Primary Prevention of CV Disease in DM
Cholesterol Recommendations
Primary Prevention
• In adult patients, lipid levels should be measured at least annually
and more often if needed to achieve goals. In adults <40 years of age
with low-risk lipid values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, and
triglycerides <150 mg/dL), lipid assessments may be repeated every 2
years.
• Lifestyle modification deserves primary emphasis for all individuals.
Patients should focus on the reduction of saturated fat and cholesterol
intake, weight loss (if indicated), and increases in dietary fiber and
physical activity. These lifestyle changes have been shown to improve
the lipid profile.
AHA=American Heart Association, CV=Cardiovascular, DM=Diabetes mellitus, HDLC=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol
Source: Buse JB et al. Circulation 2007;115:114-126
AHA Primary Prevention of CV Disease in DM
Cholesterol Recommendations (Continued)
Primary Prevention
• In those >40 years of age without overt CVD, but with >1 major CVD
risk factor*, the primary goal is an LDL-C level <100 mg/dL. If LDL-C
lowering drugs are used, a reduction of at least 30-40% in LDL-C levels
should be obtained. If the baseline LDL-C level is <100 mg/dL, statin
therapy should be initiated based on risk factor assessment and clinical
judgment.
• In those <40 years of age without overt CVD, but at increased risk of
CVD either by clinical judgment or by risk calculator, the LDL-C goal is
<100 mg/dL, and LDL-C lowering drugs should be considered if lifestyle
changes do not achieve the goal.
*Includes cigarette smoking, hypertension [BP >140/90 mm Hg or use of antihypertensive
medication], low HDL-C cholesterol [<40 mg/dL], and family history of premature CHD [CHD in
male first-degree relative <55 years of age; CHD in female first-degree relative <65 years of age].
AHA=American Heart Association, CV=Cardiovascular,
CVD=Cardiovascular disease, DM=Diabetes mellitus, HDL-C=High
density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol
Source: Buse JB et al. Circulation 2007;115:114-126
AHA and ADA Primary Prevention of CV Disease
in DM Cholesterol Recommendations
Primary Prevention
• The ADA and AHA suggest different approaches to the management
of HDL-C and triglyceride-associated CVD risk.
• The AHA suggests that in patients with triglyceride levels of 200499 mg/dL, a non-HDL-C goal of <130 mg/dL is a secondary target.
If triglycerides are >500 mg/dL, therapeutic options include a fibrate
or niacin before LDL-C lowering therapy and treatment of LDL-C to
goal after triglyceride-lowering therapy. A non HDL-C level <130
mg/dL should be achieved if possible
• The ADA suggests lowering triglycerides to <150 mg/dL and
raising HDL-C to <40 mg/dL. In women an HDL-C goal 10 mg/dL
higher (>50 mg/dL) should be considered.
ADA=American Diabetes Association, AHA=American Heart Association,
CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus, HDLC=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol
Sources:
Buse JB et al. Circulation 2007;115:114-126
American Diabetes Association. Diabetes Care 2010;33:S11-61
ADA Cholesterol Recommendations for
Patients with Diabetes Mellitus
Primary Prevention
• In most adult patients, a fasting lipid profile should be measured at
least annually. In adults with low-risk lipid values (LDL-C <100 mg/dL,
HDL-C >50 mg/dL, and triglycerides <150 mg/dL), lipid assessments
may be repeated every 2 years.
• Lifestyle modification focusing on the reduction of saturated fat,
trans fat, and cholesterol intake; increase of omega-3 fatty acids,
viscous fiber, and plant stanols/sterols; weight loss (if indicated); and
increased physical activity should be recommended to improve the
lipid profile in patients with DM.
ADA=American Diabetes Association, DM=Diabetes mellitus, HDL-C=High density
lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
ADA Cholesterol Recommendations for
Patients with Diabetes Mellitus (Continued)
Primary and Secondary Prevention
• Statin therapy should be added to lifestyle therapy, regardless of
baseline lipid levels for diabetic patients:
o
With overt CV disease
o
Without CV disease who are over the age of 40 years and have
>1 other CV disease risk factors
• For patients at lower risk (without overt CV disease and <40 years of
age), statin therapy should be considered in addition to lifestyle therapy
if LDL-C remains >100 mg/dL or in those with multiple CV disease risk
factors.
ADA=American Diabetes Association, CV=Cardiovascular,
LDL-C=Low density lipoprotein cholesterol
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
ADA Cholesterol Recommendations for
Patients with Diabetes Mellitus (Continued)
Primary and Secondary Prevention
• In individuals without overt CV disease, the primary goal is an LDL-C
<100 mg/dL (2.6 mmol/L).
• In individuals with overt CV disease, a lower LDL-C goal of <70 mg/dL
(1.8 mmol/L), using a high dose of statin is an option.
• If drug-treated patients do not reach the above targets on maximal
tolerated statin therapy, a reduction in LDL-C of approximately 30-40%
from baseline is an alternative therapeutic goal.
• Triglyceride levels <150 mg/dL (1.7 mmol/L) and HDL-C >40 mg/dL (1.0
mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women, are desirable.
However, LDL-C targeted statin therapy remains the preferred strategy.
ADA=American Diabetes Association, CV=Cardiovascular, HDL-C=High
density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
ADA Cholesterol Recommendations for
Patients with Diabetes Mellitus (Continued)
Primary Prevention
• Triglyceride levels <150 mg/dL (1.7 mmol/L) and HDL-C >40 mg/dL
(1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women, are
desirable. However, LDL-C targeted statin therapy remains the
preferred strategy.
• If targets are not reached on maximally tolerated doses of statins,
combination therapy using statins and other lipid-lowering agents may
be considered to achieve lipid targets but has not been evaluated in
outcome studies for either CV disease outcomes or safety.
• Statin therapy is contraindicated in pregnancy.
ADA=American Diabetes Association, CV=Cardiovascular, HDL-C=High density
lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
Cholesterol Management
Recommendations (Continued)
Secondary Prevention
A lipid profile should be established in all patients, and for
hospitalized patients, lipid-lowering therapy as
recommended below should be initiated before discharge
I IIa IIb III
Lifestyle modifications including daily physical activity and
weight management are strongly recommended for all
patients
Dietary therapy for all patients should include reduced
intake of saturated fats (to <7% of total calories), trans
fatty acids (to <1% of total calories), and cholesterol (to
<200 mg/d)
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Cholesterol Management
Recommendations (Continued)
Secondary Prevention
I IIa IIb III
I IIa IIb III
In addition to therapeutic lifestyle changes, statin therapy
should be prescribed in the absence of contraindications
or documented adverse effects
An adequate dose of statin should be used that reduces
LDL-C to <100 mg/dL AND achieves at least a 30%
lowering of LDL-C
I IIa IIb III
Patients who have triglycerides >200 mg/dL should be
treated with statins to lower non–HDL-C to <130 mg/dL
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Cholesterol Management
Recommendations (Continued)
Secondary Prevention
I IIa IIb III
I IIa IIb III
I IIa IIb III
Patients who have triglycerides >500 mg/dL should be
started on fibrate therapy in addition to statin therapy to
prevent acute pancreatitis
If treatment with a statin (including trials of higher-dose
statins and higher-potency statins) does not achieve the
goal selected for a patient, intensification of LDL-C–
lowering drug therapy with a bile acid sequestrant or
niacin is reasonable
For patients who do not tolerate statins, LDL-C–lowering
therapy with bile acid sequestrants and/or niacin is
reasonable
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Cholesterol Management
Recommendations (Continued)
I IIa IIb III
Secondary Prevention
It is reasonable to treat very high-risk* patients with statin
therapy to lower LDL-C to <70 mg/dL
I IIa IIb III
I IIa IIb III
In patients who are at very high risk* and who have
triglycerides >200 mg/dL, a non–HDL-C goal of <100
mg/dL is reasonable
The use of ezetimibe may be considered for patients who
do not tolerate or achieve target LDL-C with statins, bile
acid sequestrants, and/or niacin
*Presence of established CVD plus 1) multiple major risk
factors (especially diabetes), 2) severe and poorly controlled
risk factors (especially continued cigarette smoking), 3)
multiple risk factors of the metabolic syndrome (especially
high triglycerides >200 mg/dL plus non-HDL-C >130 mg/dL
with low HDL-C <40 mg/dL, and 4) patients with an ACS
ACS=Acute coronary syndrome, CVD=Cardiovascular
disease, HDL-C=High density lipoprotein cholesterol,
LDL-C=Low density lipoprotein cholesterol
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Cholesterol Management
Recommendations (Continued)
Secondary Prevention
I IIa IIb III
For patients who continue to have an elevated non-HDL-C
while on adequate statin therapy, consider niacin or fibrate
therapy
For all patients, it may be reasonable to recommend
omega-3 fatty acids from fish or fish oil capsules
(1 gram/day) for CV disease risk reduction
CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446