1 cholesterol, cholesterol therapies, and cholesterol guidelines andrew p. defilippis, ty j....
TRANSCRIPT
1
Cholesterol, Cholesterol Therapies, Cholesterol, Cholesterol Therapies, and Cholesterol Guidelinesand Cholesterol Guidelines
Andrew P. DeFilippis, Ty J. Gluckman, James Mudd, Catherine Campbell, Vera
Bittner, Gregg Fonarow & Roger S. Blumenthal
2
Doi H et al. Circulation 2000;102:670-676Colome C et al. Atherosclerosis 2000;149:295-302 Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994
HDLLDLChylomicrons,VLDL, and
their catabolic remnants
> 30 nm 20–22 nm
Potentially pro-inflammatory
9–15 nm
Potentiallyanti-inflammatory
Lipoprotein ClassesLipoprotein Classes
3
The Role of Lipoproteins in AtherogenesisThe Role of Lipoproteins in Atherogenesis
HDL
Liver Oxidativemodification
of LDL
LDL+
VLDL
Cholesterolexcreted
High plasmaLDL
LDL infiltrationinto intima
+Macrophages
Foam cells
Fatty streak
Advancedfibrocalcific
lesion
Endothelialinjury
Adherenceof platelets
Releaseof PDGF
Othergrowthfactors
LCATAPO-A1
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
(-)
4
3.7
2.9
2.2
1.7
1.3
1.0
40 70 100 130 160 190
Re
lativ
e R
isk
for
Co
ron
ary
H
ea
rt D
isea
se (
Lo
g S
cale
)
LDL-Cholesterol (mg/dL)
Grundy S et al. Circulation 2004;110:227-39
CHD Risk According to LDL-C LevelCHD Risk According to LDL-C Level
CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol
5
Therapies to Lower LDL-CTherapies to Lower LDL-C
Soluble fiber
Soy protein
Stanol esters
Dietary Adjuncts
Ezetimibe (Zetia)Cholesterol absorption inhibitor
Cholestyramine (generic and Questran)
Colesevelam (Welchol)
Colestipol (Colestid)
Bile acid sequestrants
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]
Drug(s)Class
Nicotinic acid Niacin
6
HMG-CoA Reductase Inhibitor: Mechanism of ActionHMG-CoA Reductase Inhibitor: Mechanism of Action
AcetylCoA
HMG-CoA
Mevalonate Farnesylpyrophosphate
Squalene Cholesterol
Squalenesynthase
Dolichol
Farnesyl-transferase
Farnesylatedproteins
E,E,E-Geranylgeranylpyrophosphate
Geranylgeranylatedproteins
Ubiquinones
HMG-CoA Reductase
Inhibition of the Cholesterol Biosynthetic Pathway
7
LDL-R–mediated hepatic uptake of LDL and VLDL remnants
Serum VLDL remnants
Serum LDL-C
Cholesterol synthesis
LDL receptor (B–E receptor) synthesis
Intracellular Cholesterol
Apo B
Apo E
Apo B
Systemic CirculationHepatocyteThe 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
LDLLDL
Serum IDL
VLDLRVLDLR
VLDL
HMG-CoA Reductase Inhibitor: Mechanism of ActionHMG-CoA Reductase Inhibitor: Mechanism of Action
8Illingworth DR. Med Clin North Am 2000;84:23-42
37
19
35
27
28
18
12
12
6
12
0 10 20 30 40 50 60
Atorvastatin 10/80
Fluvastatin 20/80
Simvastatin 20/80
Pravastatin 20/40
Lovastatin 20/80
Reduction of LDL Cholesterol (%)
HMG-CoA Reductase Inhibitor: Dose-Dependent EffectHMG-CoA Reductase Inhibitor: Dose-Dependent Effect
The Rule of 6’s
Each doubling of the statin dose produces an additional 6% (approximate) reduction in the LDL-C level
9Law MR et al. BMJ 2003;326:1423-1427
78 (42)69 (37)60 (32)51 (27)Simvastatin
108 (58)99 (53)90 (48)80 (43)Rosuvastatin§
62 (33)53 (29)45 (24)37 (20)Pravastatin
83 (45)68 (37)54 (29)39 (21)Lovastatin‡
61 (33)50 (27)39 (21)29 (15)Fluvastatin
102 (55)91 (49)80 (43)69 (37)Atorvastatin
80 mg/d40 mg/d20 mg/d10 mg/d Statin
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
A Meta-analysis of 164 Trials*†
HMG-CoA Reductase Inhibitor: Reduction in LDL-CHMG-CoA Reductase Inhibitor: Reduction in LDL-C
FDA=Food and Drug Administration, LDL-C=Low density lipoprotein cholesterol, Rx=Treatment
10
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
HMG-CoA Reductase Inhibitor Trials: ChronologyHMG-CoA Reductase Inhibitor Trials: Chronology
Study Population:
Primary preventionAcute coronary syndromesChronic Coronary heart disease
11
HMG-CoA Reductase Inhibitor: Primary PreventionHMG-CoA Reductase Inhibitor: Primary Prevention
West of Scotland Coronary Prevention Study (WOSCOPS)
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction
Shepherd J et al. NEJM 1995;333:1301-1307
Placebo
7.5
Pravastatin
9
6
3
0
5.3
P<0.001
31% RRRR
ate
of M
I or
CH
D
deat
h (%
)
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
12
Rat
e of
MI,
unst
able
an
gina
, or
SC
D (
%)
Placebo
5.5
Lovastatin
6
4
2
0
3.5
HMG-CoA Reductase Inhibitor: Primary PreventionHMG-CoA Reductase Inhibitor: Primary PreventionAir Force/Texas Coronary Atherosclerosis Prevention Study
(AFCAPS/TEXCAPS)
P<0.001
37% RRR
MI=Myocardial infarction, RRR=Relative risk reduction, SCD=Sudden cardiac death
Downs JR et al. JAMA 1998;279:1615–1622
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
13
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Arm (ALLHAT-LLA)
RR, 0.99; P=0.88
1 2 3 4 5 6
32% cross-over among patients with CHD
Cum
ulat
ive
rate
%
PravastatinUsual care
ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007
CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk
0
3
6
9
12
15
18
Years
10,355 patients with HTN and >1 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
HMG-CoA Reductase Inhibitor: Primary PreventionHMG-CoA Reductase Inhibitor: Primary Prevention
14
Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA)
Sever PS et al. Lancet. 2003;361:1149-1158
0
1
2
3
4
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Atorvastatin 90 mg/dl*
Placebo 126 mg/dl*
P=0.0005
Cum
ulat
ive
inci
denc
e of
M
I and
fata
l CH
D (
%)
Follow-up (yr)
36% RRR
*Post-treatment LDL-C level
CHD=Coronary heart disease, RR=Relative risk
HMG-CoA Reductase Inhibitor: Primary PreventionHMG-CoA Reductase Inhibitor: Primary Prevention
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
15O’Keefe JH Jr et al. JACC 2004;43:2142-6
–1
10
0
2
4
6
8
Statin
PlaceboWOSCOPS
AFCAPS
LDL cholesterol (mg/dL)
55 1951751551351159575
CH
D e
vent
rat
e (%
)
WOSCOPS
ASCOT
AFCAPS
ASCOT
P=0.0019
Relationship between LDL-C Levels and Event Rates in Primary Prevention Statin Trials
HMG-CoA Reductase Inhibitor: Primary PreventionHMG-CoA Reductase Inhibitor: Primary Prevention
AFCAPS= Air Force/Texas Coronary Atherosclerosis Prevention Study, ASCOT= Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, WOSCOPS= West of Scotland Coronary Prevention Study
16
0
5
10
15
Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
17.4%
14.8%
RR=0.84, P=0.048
Com
bine
d ca
rdio
vasc
ular
ev
ent r
ate
(%)*
Weeks
*Includes death, MI resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia requiring emergency rehospitalization.
4 8 12 160
Atorvastatin
Placebo
Schwartz GG et al. JAMA 2001;285:1711-1718
3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo for 16 weeks
Acute intensive treatment significantly reduces event rates
17
Follow-up (months)
3 6 9 12 15 18 21 24 27 30
30
25
20
15
10
5
0
P =0.005
Rec
urre
nt M
I, ca
rdia
c de
ath,
U
A, r
evas
cula
rizat
ion,
or
stro
ke
16% RRR
Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study
Atorvastatin
Pravastatin
ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, UA=Unstable angina
Cannon CP et al. NEJM 2004;350:1495-1504
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
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
18
Time from randomization (months)
Cum
ulat
ive
even
t ra
te (
%)*
0
5
10
15
20
0 4 8 12 16 20 24
Aggrastat to Zocor (A to Z) Trial
de Lemos JA et al. JAMA 2004;292:1307-1316
*Includes CV death, MI, readmission for an ACS, and CVA
Placebo + Simvastatin 20 mg/day
Simvastatin 40/80 mg/day
HR=0.89, P=0.14
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
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
19
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
Scandinavian Simvastatin Survival Study (4S)
Mor
talit
y (%
)
Placebo
11.5
Simvastatin
12
8
4
0
8.2
P<0.001
30% RRR
4S Group. Lancet 1994;344:1383–1389
MI=Myocardial infarction, RRR=Relative risk reduction
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
20
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
Cholesterol and Recurrent Events (CARE) Study
Placebo
13.2
Pravastatin
15
10
5
0
10.2
P=0.003
24% RRRR
ate
of M
I or
CH
D
deat
h (%
)
Sacks FM et al. NEJM 1996;335:1001–1009
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction
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
21
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary PreventionLong-term Intervention with Pravastatin in Ischemic Disease
(LIPID) Study
CH
D D
eath
(%
)
Placebo
8.3
Pravastatin
9
6
3
0
6.4
P<0.001
24% RRR
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction
LIPID Study Group. NEJM 1998;339:1349–1357
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
22
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%)
Event Rate Ratio (95% CI)Statin Better Statin Worse
0.4 0.6 0.8 1.0 1.2 1.4
0.76 (0.72–0.81)P<0.0001
Heart Protection Study (HPS)
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus,
HPS Collaborative Group. Lancet 2002;360:7-22
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
23Shepherd J et al. Lancet 2002;360:1623-1630
0
10
20
0 1 2 3 4
CH
D d
eath
, non
-fat
al
MI,
stro
ke (
%)
Years
Placebo
Pravastatin
15% RRR, P=0.014
Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction
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
24
Years
Maj
or C
V E
vent
* (%
)
0 1 2 3 4 5 6
P<0.001
22% RRR
Treating to New Targets (TNT) Trial
Atorvastatin (10 mg)
Atorvastatin (80 mg)
CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
LaRosa JC et al. NEJM 2005;352:1425-35
*Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke
0.00
0.05
0.10
0.15
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
25
Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
Cum
ulat
ive
Haz
ard
(%)
Years Since Randomization
0 1 2 3 4 5
4
8
12
HR=0.89, P=0.07
Simvastatin (20 mg)
Atorvastatin (80 mg)
Pedersen et al. JAMA 2005;294:2437-2445
HR=Hazard ratio, MI=Myocardial infarction
*Includes coronary death, hospitalization for nonfatal acute MI, or cardiac arrest with resuscitation
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
26LaRosa JC et al. NEJM 2005;352:1425-1435
CARE=Cholesterol and Recurrent Events Trial, HPS=Heart Protection Study, LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study, TNT=Treating to New Targets
30
25
20
15
10
5
00 70 90 110 130 150 170 190 210
LDL-C (mg/dL)
TNT (atorvastatin 80 mg/d)TNT (atorvastatin 10 mg/d)
HPSCARE
LIPIDLIPID
CAREHPSE
vent
(%
) 4S
4SStatinPlacebo
Relationship between LDL-C Levels and Event Rates in Secondary Prevention Statin Trials of Patients with Stable CHD
HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary Prevention
LDL-C=Low density lipoprotein cholesterol
27Cannon CP et al. JAMA 2005;294:2492-2494
RR in MI or CHD Death (%)
RR in Primary End Point (%)
LDL-C Reduction (mg/dL)
Duration (years)
PopulationTrial
1111235Stable CAD (N = 8888)
IDEAL
2122245Stable CAD (N =10,001)
TNT
1511142ACS (N = 4497)
A to Z
1616332ACS (N = 4162)
PROVE IT-TIMI 22
HMG-CoA Reductase Inhibitor: Intensive TherapyHMG-CoA Reductase Inhibitor: Intensive Therapy
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
28
• 1.4% incidence of elevated hepatic transaminases (1.1% incidence in control arm)
• Dose-dependent phenomenon that is usually reversible
• 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)
Kashani A et al. Circulation 2006;114:2788-97
74,102 subjects in 35 randomized clinical trials with statins
*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.
Hepatocyte
Skeletal myocyte
HMG-CoA Reductase Inhibitor: Adverse EffectsHMG-CoA Reductase Inhibitor: Adverse Effects
29
Concomitant Use of Meds
Fibrate
Nicotinic acid (Rarely)
Cyclosporine
Antifungal azoles**
Macrolide antibiotics†
HIV protease inhibitors
Nefazadone
Verapamil, Amiodarone
Other Conditions
Advanced age (especially >80 years)
Women > Men especially at older age
Small body frame, frailty
Multisystem disease‡
Multiple medications
Perioperative period
Alcohol abuse
Grapefruit juice (>1 quart/day)
HMG-CoA Reductase Inhibitor: Adverse EffectsHMG-CoA Reductase Inhibitor: Adverse Effects
Risk Factors for the Development of Myopathy*
Pasternak RC et al. Circulation 2002;106:1024-1028
*General term to describe diseases of muscles**Itraconazole, Ketoconazole†Erythromycin, Clarithromycin‡Chronic renal insufficiency, especially from diabetes mellitus
30
Gall Bladder
LDL Receptors
VLDL and LDL removal
Cholesterol 7- hydroxylase Conversion of cholesterol to BA BA Secretion
Liver
BA Excretion
Terminal Ileum
Bile Acid
Enterohepatic Circulation
Reabsorption of bile acids
Bile Acid Sequestrant: Mechanism of ActionBile Acid Sequestrant: Mechanism of Action
LDL-CBA=Bile acid, LDL-C=Low density lipoprotein cholesterol, VLDL=Very low density lipoprotein cholesterol
31
Bile Acid Sequestrant: Efficacy at Reducing LDL-CBile Acid Sequestrant: Efficacy at Reducing LDL-C
Insull W et al. Mayo Clin Proc 2001;76:971-82
*P<0.001 vs placebo†P=0.04 vs placebo
5
-1
0
10
3
-15
-20
-15
-10
-5
0
5
10
15
% C
hang
e fr
om b
asel
ine
at w
eek
24TGHDL-CLDL-C
*
†
Placebo
Colesevelam 3.8 grams/day
32
Bile Acid Sequestrant: Primary PreventionBile Acid Sequestrant: Primary Prevention
Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT)
Placebo
8.6
Cholestyramine
9
6
3
0
7.0
P<0.05
19% RRR
Rat
e of
MI o
r C
HD
de
ath
(%)
The LRC-CPPT Investigators. JAMA 1984;251:351-64
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction
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
33
Dietary cholesterol
Production in liver Absorption from intestine
Bloodstream
LDL-C VLDL
Cholesterolsynthesis
Biliary cholesterol
Chylomicrons
Fecal sterols and neutral sterols
Ezetimibe: Mechanism of ActionEzetimibe: Mechanism of Action
34
LDL-C
Mea
n %
cha
nge
from
base
line
to w
eek
12
–20
–15
–10
–5
0
+5
–18
+1
Triglycerides*
–8
0
HDL-C
–2
+1.0
Placebo
Ezetimibe 10 mg
Ezetimibe: Efficacy at Reducing LDL-CEzetimibe: Efficacy at Reducing LDL-C
Pooled Phase III Study Results
*Median % change
Knopp RH. Int J Clin Pract 2003;57:363-8
35
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%
Dietary Adjuncts: Efficacy at Reducing LDL-CDietary Adjuncts: Efficacy at Reducing LDL-C
Jones PJ. Curr Atheroscler Rep 1999;1:230-235Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214Rambjor GS et al. Lipids 1996;31:S45-S49Ripsin CM et al. JAMA 1992;267:3317-3325
36Jenkins DJ et al. JAMA 2003;290:502-10
Diet Evidence: Effect on Lipid Parameters and CRPDiet Evidence: Effect on Lipid Parameters and CRP
0
10
20
30
-50
-40
-30
-20
-10
0 2 4 0 2 4 0 2 4
LDL-C
Cha
nge
from
Bas
elin
e (%
) LDL-C:HDL-C CRP
Weeks Weeks Weeks
Low fat diet
Statin
Dietary portfolio*
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
*Enriched in plant sterols, soy protein, viscous fiber, and almonds
37
Liver Circulation
HDL
Serum VLDL results in reduced lipolysis to LDL
Serum LDL
VLDL
Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in reduced LDL-C levels and increased HDL-C levels
VLDL secretion
Apo B
Hepatocyte Systemic Circulation
Mobilization of FFA
TG synthesis
VLDL
LDL
Nicotinic Acid: Mechanism of ActionNicotinic Acid: Mechanism of Action
FFA=Free fatty acids, HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride, VLDL=Very low density lipoprotein
38
-50
-40
-30
-20
-10
0
10
20
30
Ch
ang
e fr
om
Ba
selin
e
Goldberg A et al. Am J Cardiol 2000;85:1100-1105
500
HDL-C
LDL-C
TG
–9%–14%
–22% –21%–17%
30%30%26%
22%15%
10%
–28%
–35%
–44%–39%
–11%
–5%
Nicotinic Acid: Efficacy at Raising HDL-CNicotinic Acid: Efficacy at Raising HDL-C
1000 1500 2000 2500Dose (mg) 3000
39
P=0.0012
100908070605040
0 2 4 6 8 10 12 14 16
Years of follow-up
Sur
viva
l (%
)
Canner PL et al. JACC 1986;8:1245–1255
Nicotinic acid stopped
Nicotinic Acid: Secondary PreventionNicotinic Acid: Secondary Prevention
Coronary Drug Project (CDP)
Nicotinic AcidPlacebo
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
MI=Myocardial infarction
40Brown BG et al. NEJM 2001;345:1583-92
Nicotinic Acid: Secondary PreventionNicotinic 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
41
0.0
0.5
1.0
1.5
2.0
2.5
3.0
50 100 150 200 250 300 350 400
MenWomen
RR
Triglyceride Level (mg/dL)
Castelli WP. Can J Cardiol 1988;4:5A-10A
CHD Risk According to Triglyceride LevelsCHD Risk According to Triglyceride Levels
Framingham Study
CHD=Coronary heart disease, RR=Relative Risk
42
Fibrate: Mechanism of ActionFibrate: Mechanism of Action
Liver
TG
IDL
VLDL
LPL
CECE FCFC
MacrophageMature HDL
Nascent HDL
LDL-R
Intestine
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+
+
43
Fibrate: Efficacy at Reducing TriglycerideFibrate: Efficacy at Reducing Triglyceride
Goldberg AC et al. Clin Ther 1989;11:69–83
1520
-46
45
23
-55-60
-50
-40
-30
-20
-10
0
10
20
30
40
50
TG = 350–499 mg/dL TG = 500–1500 mg/dL
Mea
n %
cha
nge
from
bas
elin
e
TG=Triglyceride level
147 patients with type IV/V hyperlipoproteinemia randomized to fenofibrate (100 mg three times daily) or placebo for 8 weeks
LDLTG
HDLTG
HDLLDL
44
Frick MH et al. NEJM 1987;317:1237-1245Manninen V et al. Circulation 1992;85:37-45BIP Study Group. Circulation 2000;102:21-27Rubins HB et al. NEJM 1999;341:410-418
*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)
0
5
10
15
20
25
30%
CH
D D
eat
h/N
onfa
tal M
I Rx
Placebo
2.7 4.1***
2.7
8
13.615
13
22
17
22***
66%
34%
9%
42% 22%
PRIMARY PREVENTION SECONDARY PREVENTION
HHS HHS* BIP BIP** VA-HIT
Fibrate: Primary and Secondary PreventionFibrate: Primary and Secondary Prevention
45
Fibrate: Secondary PreventionFibrate: Secondary Prevention
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)
CH
D D
eath
or
Non
fata
l MI (
%)
Placebo
5.9
Fenofibrate
9
6
3
0
5.2
P=0.16
11% RRR
9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 yrs
Fenofibrate fails to provide significant additional benefit*
Keech A et al. Lancet 2005;366:1849-61
*Unadjusted for concomitant statin use
CHD=Coronary heart disease, MI=Myocardial infarction
46
HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglycerides *Daily dose of 40mg of each drug, excluding rosuvastatin
Good 9%1%18% 13%Ezetimibe
Good 14-29% 4-12% 25-50% 19-37%Statins*
Good30%11-13%4-21%19%Fibrates
Reasonable to Poor
30-70% 14-35% 10-20% 10-20%Nicotinic acid
PoorNeutral or 3%10-18%7-10%Bile acid sequestrants
Patient tolerability
TGHDL-CLDL-CTCTherapy
Cholesterol Management PharmacotherapyCholesterol Management Pharmacotherapy
47
% R
edu
ctio
n
Triglyceride
*P<0.05
-10 -20 -30 -40 -50
0
-46*
-21*
Total Cholesterol
Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731
-3 Fatty Acids: Efficacy at Reducing Triglyceride-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
48Yokoyama M et al. Lancet. 2007;369:1090-8
-3 Fatty Acids: Primary and Secondary Prevention-3 Fatty Acids: Primary and Secondary Prevention
JELIS Trial18,645 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
49
*Post myocardial infarction
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
7.0%
8.0%
DART* (n=3,482) GISSI* (n=11,324)
N-3 Fatty Acids
Placebo
-3 Fatty Acids: Secondary Prevention-3 Fatty Acids: Secondary Prevention
Burr ML et al. Lancet 1989;2:757-761GISSI Investigators. Lancet 1999;354:447-455
Diet and Reinfarction Trial (DART)Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
miocardico (GISSI)
All
cau
se m
ort
alit
y (%
)
-3 fatty acids reduce mortality post MI
50
4.0
3.0
2.0
1.0
25 45 65HDL-C (mg/dL)
CH
D r
isk
ratio
2.0
1.0
0
4.0
CHD Risk According to HDL-C LevelsCHD Risk According to HDL-C Levels
Framingham Study
Kannel WB. Am J Cardiol 1983;52:9B–12B
CHD=Coronary heart disease, HDL-C=High-density lipoprotein cholesterol
51
0 10 20
2 RFs
0-1 RFs
CAD or Risk Equivalent**
Risk Profile Assessment for LDL-C Lowering Risk Profile Assessment for LDL-C Lowering
A risk assessment tool* is needed for individuals with >2 RFs
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-97
CAD=Coronary artery disease, CHD=Coronary heart disease, DM=Diabetes mellitus, RF=Risk factor
**Includes DM, non-coronary atherosclerotic vascular disease, and >20% 10-year CHD risk by the FRS
*Such as the Framingham Risk Score (FRS)
10-year CHD Risk
52
Years Points
20-34 -935-39 -440-44 045-49 350-54 655-59 860-64 1065-69 1170-74 1275-79 13
Step 1: Age Points
TC (mg/dl)
Age 20-39
Age 40-49
Age 50-59
Age 60-69
Age 70-79
<160 0 0 0 0 0160-199 4 3 2 1 0200-239 7 5 3 1 0240-279 9 6 4 2 1
>280 11 8 5 3 1
Framingham Risk Score: MenFramingham Risk Score: Men
Step 2: Total Cholesterol Points
HDL-C (mg/dl) Points
>60 -150-59 040-49 1<40 2
Step 3: HDL-C Points
SBP (mmHg)
If untreated
If treated
<120 0 0120-129 0 1130-139 1 2140-159 1 2
>160 2 3
Step 4: SBP PointsAge
20-39Age
40-49Age
50-59Age
60-69Age
70-79
Nonsmoker 0 0 0 0 0
Smoker 8 5 3 1 1
Step 5: Smoking Status Points
AgeTotal Cholesterol
HDL-CSystolic Blood Pressure
Smoking Status
Point Total
Step 6: Sum of Points
Point Total
10-year Risk
Point Total
10-year Risk
Point Total
10-year Risk
<0 <1% 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% >17 >30%
4 1% 11 8%
5 2% 12 10%
Step 7: 10-year CHD Risk
53
Years Points
20-34 -735-39 -340-44 045-49 350-54 655-59 860-64 1065-69 1270-74 1475-79 16
Step 1: Age Points
TC (mg/dl)
Age 20-39
Age 40-49
Age 50-59
Age 60-69
Age 70-79
<160 0 0 0 0 0160-199 4 3 2 1 1200-239 8 6 4 2 1240-279 11 8 5 3 2
>280 13 10 7 4 2
Framingham Risk Score: WomenFramingham Risk Score: Women
Step 2: Total Cholesterol Points
HDL-C (mg/dl) Points
>60 -150-59 040-49 1<40 2
Step 3: HDL-C Points
SBP (mmHg)
If untreated
If treated
<120 0 0120-129 1 3130-139 2 4140-159 3 5
>160 4 6
Step 4: SBP PointsAge
20-39Age
40-49Age
50-59Age
60-69Age
70-79
Nonsmoker 0 0 0 0 0
Smoker 9 7 4 2 1
Step 5: Smoking Status Points
AgeTotal Cholesterol
HDL-CSystolic Blood Pressure
Smoking Status
Point Total
Step 6: Sum of Points
Point Total
10-year Risk
Point Total
10-year Risk
Point Total
10-year Risk
<9 <1% 15 3% 22 17%
9 1% 16 4% 23 22%
10 1% 17 5% 24 27%
11 1% 18 6% >25 >30%
12 1% 19 8%
13 2% 20 11%
14 2% 21 14%
Step 7: 10-year CHD Risk
54
Risk Category LDL-C Goal Initiate TLCConsider
Drug Therapy
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-lowering drug optional)
Grundy S et al. Circulation 2004;110:227-39
ATP III LDL-C Goals and Cut-points for Drug TherapyATP III LDL-C Goals and Cut-points for Drug Therapy
ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes
*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
55
Level (mg/dl) Classification
<200 Desirable
200-239 Borderline High
>240 High
Level (mg/dl) Classification
<40 Desirable
40-50 Borderline High
>50 High
Level (mg/dl) Classification
<150 Normal
150-199 Borderline High
200-499 High
>500 Very High
ATP III Classification of Other Lipoprotein LevelsATP III Classification of Other Lipoprotein Levels
Total Cholesterol HDL-Cholesterol
Triglyceride
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-97
56
Cholesterol Management Guidelines (Continued)Cholesterol Management Guidelines (Continued)
Goals Recommendations
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 (<7% of total calories) and cholesterol (<200 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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-97
LDL-C=Low density lipoprotein cholesterol, NCEP=National Cholesterol Education Program
57
Cholesterol Management Guidelines (Continued)Cholesterol Management Guidelines (Continued)
Goals Recommendations
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 >150 mg/dl or the HDL-C level is <40 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 >500 mg/dl, nicotinic acid or a fibrate should be considered before starting LDL-C lowering therapy
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-97
HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, NCEP=National Cholesterol Education Program, TG=Triglyceride
58
Secondary Prevention
Cholesterol Management GuidelinesCholesterol Management Guidelines
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Restriction of saturated fat (<7% of total calories), trans-fatty acids, and cholesterol (<200 mg/day) in all patients
Promotion of daily physical activity and weight management in all patients
Increase in -3 fatty acid consumption in all patients
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
59
Secondary Prevention
Cholesterol Management Guidelines (Continued)Cholesterol Management Guidelines (Continued)
Initiation or intensification of LDL-C lowering drug therapy in those with a baseline or on-treatment LDL-C level >100 mg/dl
Intensification of LDL-C lowering drug therapy to achieve a LDL-C <70 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 <70 mg/dl
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
LDL-C=Low density lipoprotein cholesterol
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
60
Secondary Prevention
Cholesterol Management Guidelines (Continued)Cholesterol Management Guidelines (Continued)
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 >500 mg/dl
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride
61
Secondary Prevention
Cholesterol Management Guidelines (Continued)Cholesterol Management Guidelines (Continued)
Reduction of non-HDL-cholesterol to <130 mg/dl in those with a TG level of 200-499 mg/dl
Reduction of non-HDL-cholesterol to <100 mg/dl in those with a TG level of 200-499 mg/dl
HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
62
Secondary Prevention
Cholesterol Management Guidelines (Continued)Cholesterol Management Guidelines (Continued)
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)
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol