New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and...
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Transcript of New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and...
New Concepts in the EvaluationNew Concepts in the Evaluation and and
Treatment of DyslipidemiaTreatment of Dyslipidemia
Nathan D. Wong, PhD, FACCNathan D. Wong, PhD, FACC
Professor and DirectorProfessor and Director
Heart Disease Prevention ProgramHeart Disease Prevention Program
Division of CardiologyDivision of Cardiology
University of California, IrvineUniversity of California, Irvine
Past President, American Society Past President, American Society for Preventive Cardiologyfor Preventive Cardiology
1.20
1.100
1.063
1.019
1.006
0.95
5 10 20 40 60 80 1000
ChylomicronRemnants
VLDL
LDL-R
HDL2
HDL3DL3
Particle Size (nm)
Den
sity
(g/
ml)
Chylomicron
VLDLRemnants
Lipoprotein ParticlesLipoprotein Particles
Lp(a)
IDL
Only these lipoprotein particles found in plaque at biopsy.
1.050
Rationale for therapeutic lowering of Apo B lipoproteins: decrease the probability of inflammatory response to retention
High Plasma Apo B Lipoprotein High Plasma Apo B Lipoprotein Levels Promote AtherogenesisLevels Promote Atherogenesis
BloodApo B lipoproteinparticles
ModificationMacrophage
Monocytes bind toadhesion molecules
Smooth muscle
Foam cell
Inflammatory response
Lipid Atherogenesis
HDL
Liver
Advancedfibrocalcific
lesion
Oxidativemodification
of LDL
LDL+
VLDL
Cholesterolexcreted
Endothelialinjury
Adherenceof platelets
Releaseof PDGF
High plasmaLDL
LDL infiltrationinto intima
+Macrophages
Foam cells
Fatty streak
LCATAPO-A1
Othergrowthfactors
lipid core
adventitia
adventitia
lipid core
Anti-atherosclerotic therapy
From Davies et al (1998)
Unstablelesion
Stablelesion
Proportion of U.S. Adults at Recommended Proportion of U.S. Adults at Recommended Lipid Levels in NHANES 2003-2004Lipid Levels in NHANES 2003-2004
0
10
20
30
40
50
60
70
80
Percent of Adults
LDL-C HDL-C TG All
Men
Women
CVD
DM
Ghandehari and Wong et al, Am Heart J 2008
Genetic Causes of DyslipidemiaGenetic Causes of Dyslipidemia
Type I – Familial HyperchylomicronemiaType I – Familial Hyperchylomicronemia Fasting triglycerides > 1000 mg/dlFasting triglycerides > 1000 mg/dl Defect in lipoprotein lipase or apo CIIDefect in lipoprotein lipase or apo CII Not necessarily at increased risk of CADNot necessarily at increased risk of CAD
Type II - Familial Hypercholesterolemia (type II)Type II - Familial Hypercholesterolemia (type II) LDL-C > 95LDL-C > 95thth percentile for age and gender percentile for age and gender CAD in men by 3CAD in men by 3rdrd or 4 or 4thth decade decade Defect in LDL receptorDefect in LDL receptor Autosomal dominant inheritanceAutosomal dominant inheritance Prevalence 1:500Prevalence 1:500
Familial Defective apo B 100Familial Defective apo B 100 Defective apo B alters LDLr handlingDefective apo B alters LDLr handling Previously undetecable from FHPreviously undetecable from FH
Genetic Causes of DyslipidemiaGenetic Causes of Dyslipidemia
Type III – HyperlipoproteinemiaType III – Hyperlipoproteinemia Increased TC, VLDL, decreased HDL; Increased VLDL:TG Increased TC, VLDL, decreased HDL; Increased VLDL:TG Defect in apo E results in increased concentration of remnant particlesDefect in apo E results in increased concentration of remnant particles RareRare
Type IV – Familial HypertriglyceridemiaType IV – Familial Hypertriglyceridemia Increased TC (due to VLDL), TG, decreased LDL, HDLIncreased TC (due to VLDL), TG, decreased LDL, HDL Results from hepatic overproduction of VLDLResults from hepatic overproduction of VLDL Prevalence 1:100 – 1:50; Association with CAD not as strong as FHPrevalence 1:100 – 1:50; Association with CAD not as strong as FH Heterogeneous inheritanceHeterogeneous inheritance Very sensitive to diet and EtOHVery sensitive to diet and EtOH
Type VType V Increase in chylomicrons and VLDLIncrease in chylomicrons and VLDL RareRare
Genetic Causes of DyslipidemiaGenetic Causes of Dyslipidemia
Familial Combined HyperlipidemiaFamilial Combined Hyperlipidemia Increased TC, LDL and/or triglycerides; decreased HDL Increased TC, LDL and/or triglycerides; decreased HDL Most common genetic dyslipidemia: prevalence 1:50Most common genetic dyslipidemia: prevalence 1:50 Heterogenous inheritanceHeterogenous inheritance Accounts for 10-20% of patients with premature CADAccounts for 10-20% of patients with premature CAD
Defects in HDL MetabolismDefects in HDL Metabolism Most often low HDL is secondary to other dyslipidemiaMost often low HDL is secondary to other dyslipidemia Not all associated with increased CAD risk (e.g. apo AINot all associated with increased CAD risk (e.g. apo AIMilanoMilano)) Tangier’s DiseaseTangier’s Disease CETP defects result in increased HDLCETP defects result in increased HDL
Total Cholesterol Distribution: Total Cholesterol Distribution: CHD vs Non-CHD PopulationCHD vs Non-CHD Population
Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.1996 Reprinted with permission from Elsevier Science.
35% of CHD 35% of CHD Occurs in Occurs in People with People with TC<200 mg/dLTC<200 mg/dL
150 200
Total Cholesterol (mg/dL)
250 300
No CHD
CHD
Framingham Heart Study—26-Year Follow-up
Low HDL-C Levels Increase CHD Risk Even Low HDL-C Levels Increase CHD Risk Even When Total-C Is NormalWhen Total-C Is Normal
Risk of CHD by HDL-C and Total-C levels; aged 48–83 yCastelli WP et al. JAMA 1986;256:2835–2838
02468
101214
< 40 40–49 50–59 60< 200
230–259200–229
260
HDL-C (mg/dL) Tota
l-C (m
g/dL
)
14
-y in
cid
en
ce
rate
s (%
) fo
r C
HD
11.24
11.91
12.50
11.91
6.56
4.67
9.05
5.53
4.85
4.153.77
2.782.06
3.83
10.7
6.6
Sarwar N, et al. Circulation. 2007;115:450-458.
aIndividuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most)
CHD Risk Ratio* (95% CI)
1.72 (1.56–1.90)
21
Duration of follow-up≥10 years 5902<10 years 4256
SexMale 7728
Female 1994
Fasting statusFasting 7484Nonfasting 2674
Adjusted for HDL Yes 4469 No 5689
N=262,525
Groups CHD Cases
Overall CHD Risk Ratioa
Decreased Risk Increased Risk
CHD=coronary heart diseaseHDL=high-density lipoprotein
Triglyceride Level Is Significant CHD Risk Factor: Triglyceride Level Is Significant CHD Risk Factor: Recent Meta-Analysis of 29 Studies (n=262,525) Recent Meta-Analysis of 29 Studies (n=262,525) (Sarwar et al., Circulation 2007)(Sarwar et al., Circulation 2007)
Triglyceride-rich lipoproteins carry cholesterol and promote Triglyceride-rich lipoproteins carry cholesterol and promote atherosclerosis*atherosclerosis*
Very–low-density lipoprotein (VLDL) is precursor to low-density Very–low-density lipoprotein (VLDL) is precursor to low-density lipoprotein (LDL) lipoprotein (LDL)
Hypertriglyceridemia (HTG) drivesHypertriglyceridemia (HTG) drives Cholesterol esters enrichment of VLDL (more atherogenic)Cholesterol esters enrichment of VLDL (more atherogenic) ↓ ↓ LDL size (small, dense LDL are more atherogenic)*LDL size (small, dense LDL are more atherogenic)* ↓ ↓ LDL-C (small, dense LDL carry less cholesterol)*LDL-C (small, dense LDL carry less cholesterol)* ↓ ↓ High-density lipoprotein (HDL) size (small, dense HDL are unstable)High-density lipoprotein (HDL) size (small, dense HDL are unstable)
HTG is linked to other proatherogenic states*HTG is linked to other proatherogenic states* Insulin resistanceInsulin resistance Proinflammatory stateProinflammatory state Prothrombotic stateProthrombotic state Prooxidative stateProoxidative state Endothelial dysfunctionEndothelial dysfunction
*Reasons why non–HDL-C is stronger than LDL-C as predictor of cardiovascular disease
How Can Hypertriglyceridemia How Can Hypertriglyceridemia be Atherogenic?be Atherogenic?
Apolipoprotein B
LDL=130 mg/dL
Fewer Particles More Particles
Cholesterolester
More apolipoprotein B
Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.
Correlates with: TC 198 mg/dL
LDL-C 130 mg/dLTG 90 mg/dLHDL-C 50 mg/dL
Non–HDL-C148 mg/dL
Correlates with: TC 210 mg/dL
LDL-C 130 mg/dLTG 250 mg/dLHDL-C 30 mg/dL
Non–HDL-C180 mg/dLTC=total cholesterol, LDL-C=low-density lipoprotein cholesterol, TG=triglycerides, HDL-C=high-density lipoprotein cholesterol
Elevated Triglycerides Are Associated With Elevated Triglycerides Are Associated With Increased Small, Dense LDL ParticlesIncreased Small, Dense LDL Particles
Cholesterol per particle, Cholesterol per particle, BUTBUT
Subendothelial Subendothelial penetrationpenetration
Subendothelial Subendothelial bindingbinding
Oxidized/modifiedOxidized/modified
LDL-receptor clearanceLDL-receptor clearance
LDL=low-density lipoprotein
Why Is Small, Dense LDL Why Is Small, Dense LDL MoreMore Atherogenic?Atherogenic?
Significance of NonSignificance of Non--HDL-CHDL-C LDL-C levels incompletely measure the total LDL-C levels incompletely measure the total
atherogenic burdenatherogenic burden When serum TG are >200 mg/dL, increased remnant When serum TG are >200 mg/dL, increased remnant
atherogenic lipoproteins heighten risk beyond predicted atherogenic lipoproteins heighten risk beyond predicted by LDL-Cby LDL-C
– Associated with substantially elevated VLDL-CAssociated with substantially elevated VLDL-C VLDL-C and IDL-C are not accounted for by the VLDL-C and IDL-C are not accounted for by the
calculation of LDL-Ccalculation of LDL-C Non-HDL-C = cholesterol concentration of all Non-HDL-C = cholesterol concentration of all
atherogenic lipoproteinsatherogenic lipoproteins
Miller M, et al. Am J Cardiol 2009;101:1003-1008
Non-HDL-Cholesterol and CVD RiskNon-HDL-Cholesterol and CVD Risk
Very–low-density lipoprotein (VLDL)Very–low-density lipoprotein (VLDL) Made in the liverMade in the liver Triglycerides (TG) >> cholesterol esters (CE)Triglycerides (TG) >> cholesterol esters (CE) Carries lipids from the liver to peripheral tissuesCarries lipids from the liver to peripheral tissues
HDL
LDL
IDL
VLDL
Ath
erog
enic
Lip
opro
tein
sN
on-H
DL;
Apo
B-1
00—
cont
aini
ng
Intermediate-density lipoprotein (IDL)• Formed from VLDL due to lipase removal of TG• Also known as a VLDL remnant
Low-density lipoprotein (LDL) • Formed from IDL due to lipase removal of TG• CE >> TG
High-density lipoprotein (HDL)• Removes cholesterol from peripheral tissues
Lp(a)
Lipoprotein (a) • Formed from LDL w/addition of apolipoprotein A • Atherogenic and prothrombotic
Non-HDL Includes Non-HDL Includes AllAll Atherogenic Atherogenic Lipoprotein ClassesLipoprotein Classes
Lp(a) in Atherogenesis: Another Culprit?Lp(a) in Atherogenesis: Another Culprit?
Identical to LDL particle except for addition of apo(a)Identical to LDL particle except for addition of apo(a)
Plasma concentration predictive of atherosclerotic Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although disease in many epidemiologic studies, although not allnot all
Accumulates in atherosclerotic plaqueAccumulates in atherosclerotic plaque
Binds apo B-containing lipoproteins and proteoglycansBinds apo B-containing lipoproteins and proteoglycans
Taken up by foam cell precursorsTaken up by foam cell precursors
May interfere with thrombolysisMay interfere with thrombolysis
Maher VMG et al. JAMA. 1995;274:1771-1774.Stein JH, Rosenson RS. Arch Intern Med. 1997;157:1170-1176.
Lp(a): An Independent CHD Risk Factor in Men of the Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring CohortFramingham Offspring Cohort
RR=relative risk; HT=hypertension; GI=glucose intolerance.
Bostom AG et al. JAMA. 1996;276:544-548.
1.9 1.8 1.81.2
2.73.6
RR
0.1
1
10
2
5
0.2
0.5 Lp(a) TC HDL-C HT GI Smoking
Placebo - Statin outcome trialsPlacebo - Statin outcome trials
High-risk CHD patients High-risk CHD patients (high cholesterol) (high cholesterol)
Majority of Majority of CHD patients CHD patients (broad range of (broad range of cholesterol levels) cholesterol levels)
Patients at high risk Patients at high risk of CHD (highof CHD (high cholesterol)cholesterol)
Patients at low Patients at low risk of CHD risk of CHD (low HDL-C)(low HDL-C)
PrimaryPrimarypreventionprevention
SecondarySecondarypreventionprevention
WOSCOPS(pravastatin)
AFCAPS/TexCAPS(lovastatin)
4S(simvastatin)
HPS(simvastatin)
CARE (pravastatin)
LIPID(pravastatin)
Continuum Continuum of riskof risk
22.622.6
12.912.9
8.448.44
7.97.9
2.82.8Pla
ceb
o M
I ra
te p
er 1
00 s
ub
ject
s p
er 5
yea
rs
PROSPER(pravastatin)
Heart failureHeart failureCORONAGISSI-HF(rosuvastatin)
End stageEnd stage53.753.7
JUPITER(rosuvastatin)
LDL-C achieved mg/dL (mmol/L)
WOSCOPS – Placebo
AFCAPS - Placebo
ASCOT - PlaceboAFCAPS - Rx WOSCOPS - Rx
ASCOT - Rx
4S - Rx
HPS - Placebo
LIPID - Rx
4S - Placebo
CARE - Rx
LIPID - Placebo
CARE - Placebo
HPS - Rx
0
5
10
15
20
25
30
40(1.0)
60(1.6)
80(2.1)
100(2.6)
120(3.1)
140(3.6)
160(4.1)
180(4.7)
Even
t ra
te (
%)
6
Secondary Prevention
Primary Prevention
Rx - Statin therapyPRA – pravastatinATV - atorvastatin
200(5.2)
PROVE-IT - PRA
PROVE-IT – ATV
Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
LaRosa JC et al. N Engl J Med 2005;352:e-version
TNT – ATV10
TNT – ATV80
LDL cholesterol and benefit in clinical trialsLDL cholesterol and benefit in clinical trialsIs lower better ?Is lower better ?
JUPITERJUPITER
TNTTNT
Cholesterol Treatment Trialists’ (CCT) Collaboration: Cholesterol Treatment Trialists’ (CCT) Collaboration: Efficacy and safety of cholesterol-lowering treatment: Efficacy and safety of cholesterol-lowering treatment:
prospective meta-analysis fo data from 90,056 prospective meta-analysis fo data from 90,056 participants in 14 randomized trials of statins participants in 14 randomized trials of statins
(The Lancet 9/27/05)(The Lancet 9/27/05)
Over average 5 year treatment period (per mmol/L reductionOver average 5 year treatment period (per mmol/L reduction—approx 40 mg/dl in LDL-C):—approx 40 mg/dl in LDL-C): 12% reduction in all-cause mortality12% reduction in all-cause mortality 19% reduction in coronary mortality19% reduction in coronary mortality 23% reduction in MI or CHD death23% reduction in MI or CHD death 17% reduction in stroke17% reduction in stroke 21% reduction in major vascular events21% reduction in major vascular events No difference in cancer incidence (RR=1.00).No difference in cancer incidence (RR=1.00).
Statin therapy can safely reduce 5-year incidence of major Statin therapy can safely reduce 5-year incidence of major coronary events, revascularization, and stroke by about coronary events, revascularization, and stroke by about 20% per mmol/L (about 38 mg/dl) reduction in LDL-C20% per mmol/L (about 38 mg/dl) reduction in LDL-C
HPS: First Major Coronary Event
0.4 0.6 0.8 1.0 1.2 1.4
Nonfatal MI
Coronary death
Subtotal: MCE
Coronary
Noncoronary
Subtotal: any RV
Any MVE
Coronary events
Revascularizations
Type of Major Vascular Event
Statin-Allocated
(n = 10269)
Placebo-Allocated
(n = 10267)
357 (3.5%) 574 (5.6%)
587 (5.7%) 707 (6.9%)
898 (8.7%) 1212 (11.8%)
513 (5.0%) 725 (7.1%)
450 (4.4%) 532 (5.2%)
939 (9.1%) 1205 (11.7%)
2033 (19.8%) 2585 (25.2%)
0.73 (0.670.79)P < 0.0001
0.76 (0.700.83)P < 0.0001
0.76 (0.720.81)P < 0.0001
Statin Better Placebo Better
Heart Protection Study Collaborative Group. Lancet. 2002;360:722.
HPS—Simvastatin: Vascular Events by Baseline LDL-C
Baseline Baseline
LDL-C (mg/dL)LDL-C (mg/dL)Statin Statin
(n = 10,269)(n = 10,269)Placebo Placebo
(n = 10,267)(n = 10,267)
<100<100 282 (16.4%)282 (16.4%) 358 (21.0%)358 (21.0%)
100–129100–129 668 (18.9%)668 (18.9%) 871 (24.7%)871 (24.7%)
130130 1083 (21.6%)1083 (21.6%) 1356 (26.9%)1356 (26.9%)
All patientsAll patients 2033 (19.8%)2033 (19.8%) 2585 (25.2%)2585 (25.2%)
Event Rate Ratio (95% CI)Statin Better Statin Worse
0.4 0.6 0.8 1.0 1.2 1.4
www.hpsinfo.org
0.76 (0.72–0.81)P < 0.0001
Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study
3 6 9 12 15 18 21 24 27 30
Follow-up (months)
30
25
20
15
10
5
0
P =0.005
Rec
urre
nt M
I or
Car
diac
Dea
th
16% RRRAtorvastatin
Pravastatin
ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction
Cannon CP et al. NEJM 2004;350:1495-1504
HMG-CoA Reductase Inhibitor: HMG-CoA Reductase Inhibitor: Secondary PreventionSecondary Prevention
4,162 patients with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months
0
5
10
15
20
25
30
60 80 100 120 140 160 180 200
TNT: RationaleTNT: Rationale
(1.6)(1.6) (2.1)(2.1) (2.6)(2.6) (3.1)(3.1) (3.6)(3.6) (4.1)(4.1) (4.7)(4.7) (5.2)(5.2)
Atorvastatin 80 mgAtorvastatin 80 mg
Atorvastatin 10 mgAtorvastatin 10 mg
ScreeningScreening
TNTTNT
??
Adapted from LaRosa et al. Adapted from LaRosa et al. N Engl J Med. N Engl J Med. 2005:352:1425-1435. 2005:352:1425-1435.
LDL-C, mg/dL (mmol/L)LDL-C, mg/dL (mmol/L)
Pat
ien
ts W
ith
CH
D E
ven
ts (
%)
Pat
ien
ts W
ith
CH
D E
ven
ts (
%)
0
20
40
60
80
100
120
140
160 Atorvastatin 10 mg (n=5006)
Atorvastatin 80 mg (n=4995)
TNT: Changes in LDL-C by TNT: Changes in LDL-C by Treatment GroupTreatment Group
TNT: Changes in LDL-C by TNT: Changes in LDL-C by Treatment GroupTreatment Group
FinalFinalScreenScreen 00 33 1212 2424 3636 4848 6060
PP<.001<.001
BaselineBaseline
4.04.0
3.53.5
3.03.0
2.52.5
2.02.0
1.51.5
1.01.0
0.50.5
00
Mean
LD
L-C
(mm
ol/L
)M
ean L
DL
-C (m
mo
l/L)
Mean LDL-C level = 101 mg/dL (2.6 mmol/L)Mean LDL-C level = 101 mg/dL (2.6 mmol/L)
Mean LDL-C level = 77 mg/dL (2.0 mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L)
LaRosa et al. LaRosa et al. N Engl J Med.N Engl J Med. 2005;352:1425-1435. 2005;352:1425-1435.
Mea
n L
DL
-C (
mg
/dL
)M
ean
LD
L-C
(m
g/d
L)
Study Visit (Months)Study Visit (Months)
TNT: Primary Efficacy Outcome Measure: Major TNT: Primary Efficacy Outcome Measure: Major Cardiovascular Events*Cardiovascular Events*
** CHD death, nonfatal nonCHD death, nonfatal non––procedure-related MI, resuscitated cardiac arrest, procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.fatal or nonfatal stroke.LaRosa et al. LaRosa et al. N Engl J Med.N Engl J Med. 2005;352:1425-1430. 2005;352:1425-1430.
HR=0.78 (95% CI 0.69, 0.89); HR=0.78 (95% CI 0.69, 0.89); PP<.001<.001
Pro
po
rtio
n o
f P
atie
nts
Exp
erie
nci
ng
P
rop
ort
ion
of
Pat
ien
ts E
xper
ien
cin
g
Maj
or
Car
dio
vasc
ula
r E
ven
tM
ajo
r C
ard
iova
scu
lar
Eve
nt
00
0.050.05
0.100.10
0.150.15
Atorvastatin 10 mgAtorvastatin 10 mg
Atorvastatin 80 mgAtorvastatin 80 mg Relative Relative risk risk
reduction reduction
22% 22%
00 11 22 33 44 55 66Time (Years)Time (Years)
Mean LDL-C level = 77 mg/dL Mean LDL-C level = 77 mg/dL
Mean LDL-C level = 101 mg/dL Mean LDL-C level = 101 mg/dL
Meta analysis of moderate vs aggressive statin Meta analysis of moderate vs aggressive statin therapytherapy
Cannon et al (2006) JACC 48:438
Coronary death or MI
ACS
Stable CHD
Recent Coronary IVUSRecent Coronary IVUSProgression TrialsProgression Trials
-1.2
-0.6
0
0.6
1.2
1.8
50 60 70 80 90 100 110 120
Med
ian
ch
an
ge in
perc
en
t ath
ero
ma v
olu
me (
%)
Mean LDL-C (mg/dL)
REVERSALpravastatin
REVERSALatorvastatin
CAMELOTplacebo
A-Plusplacebo
ACTIVATEplacebo
Relationship between LDL-C and Progression Rate
ASTEROIDrosuvastatin
Nissen SE, Nicholls S et al. JAMA 2006;295:1555–1565
Rosuvastatin 40 mg (n=349 for IVUS analysis; n=292 for QCA analysis)
Patients (≥18 years)
CAD, undergoing coronary angiography
Target coronary artery: ≤50% reduction in lumen diameter of
≥40 mm segment
Target segment for QCA: all segments >25% at baseline
No cholesterol entry criteria
Visit:Week:
Lipids LipidsTolerability
IVUSQCA
LipidsTolerability
LipidsTolerability
TolerabilityTolerability Tolerability
1–6
20
313
426
539
652
765
878
991
10104
Eligibilityassessment
ASTEROID: Study DesignASTEROID: Study Design
IVUSQCA
Lipids
*P<0.001 for difference from baseline. Wilcoxon signed rank test
-10-9-8-7-6-5-4-3-2-10
Median atheroma volume in themost diseased 10-mm
subsegmentMedian normalized TAV
Chang
e f
rom
base
line (
%)
- 9.1%*
*- 6.8%
End Point Analysis: Change in Key IVUS Parameters
n=319 n=346
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
Example of Regression of Atherosclerosis with Example of Regression of Atherosclerosis with Rosuvastatin in ASTEROID (measured by IVUS)Rosuvastatin in ASTEROID (measured by IVUS)
Sipahi I, Nicholls S, Tuzcu E, Nissen S. Interpreting the ASTEROID trial: Coronary atherosclerosis can regress with very intensive statin therapy. Cleve Clin J Med, 2006; 73:937-944.
Reprinted with permission. Copyright 2006. Cleveland Clinic Foundation. All rights reserved.
Diabetes Mellitus:Diabetes Mellitus:Effect of an HMG-CoA Reductase Effect of an HMG-CoA Reductase InhibitorInhibitor
Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2008;37:117-25
Meta-analysis of 18,686 patients with DM randomized to treatment with a HMG-CoA Reductase Inhibitor
A statin reduces adverse CV events in diabetics
Residual CVD Risk in Statin vs Placebo Residual CVD Risk in Statin vs Placebo TrialsTrials
4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333:1301-1307.6 Downs JR et al. JAMA. 1998;279:1615-1622.
14S Group. Lancet. 1994;344:1383-1389.2LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 3Sacks FM et al. N Engl J Med. 1996;335:1001-1009.
LDLN 4444 4159 20 536 6595 66059014
-35% -28% -29% -26% -25%-25%Secondary High Risk Primary
Patie
nts
Expe
rienc
ing
Maj
or C
HD E
vent
s, %
4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/TexCAPS6
PlaceboStatin
19.4
12.310.2 8.7
5.5 6.8
28.0
15.913.2 11.8
7.910.9
Many CHD Events Still Occur in Statin-Treated Patients
25-40% CVD Reduction Leaves High Residual Risk
Antioxidative Activity
AntithromboticActivity
Potential Antiatherogenic Actions of HDL
Anti-infectious Activity
EndothelialRepair
Chapman MJ et al. Curr Med Res Opin. 2004;20:1253-1268.Assmann G et al. Annu Rev Med. 2003;53:321-341.
AntiapoptoticActivity
ReverseCholesterolTransportCellular
CholesterolEfflux
Anti-inflammatoryActivity
VasodilatoryActivity
HDL
Apo A-I
Apo A-II
Should High-Density Lipoprotein Should High-Density Lipoprotein Be a Target of Therapy?Be a Target of Therapy?
-1-0.8-0.6-0.4-0.2
00.20.40.60.8
11.21.4
MARS MAAS
PLAC I LCAS
PLAC ICCAIT
LCASMAAS
MARS
ASTEROID
CCAIT
40 45 50
*ASTEROID rosuvastatin MAAS simvastatin CCAIT lovastatin MARS lovastatin LCAS fluvastatin PLAC I pravastatin
Ch
an
ge in
% s
ten
osis
per
year
On-treatment HDL-C (mg/dL)
Change in Percent Diameter Stenosis Change in Percent Diameter Stenosis vs On-treatment HDL-C in QCA Trialsvs On-treatment HDL-C in QCA Trials
PlaceboStatin*
Ballantyne CM, Nicholls S et al. Circulation 2008; Online
Should High-Density Lipoproteins Be a Should High-Density Lipoproteins Be a Target of Therapy ?Target of Therapy ?
ATP III Guidelines on HDL-C: “Current documentation of ATP III Guidelines on HDL-C: “Current documentation of risk reduction through controlled clinical trials is not sufficient risk reduction through controlled clinical trials is not sufficient to warrant setting a specific goal value for raising HDL-C” to warrant setting a specific goal value for raising HDL-C” (Grundy SM et al. (Grundy SM et al. Circulation. Circulation. 2004;110:227-239)2004;110:227-239)
Failure of ACCORD, FIELD, AIM-HIGH and the experience Failure of ACCORD, FIELD, AIM-HIGH and the experience with torcetrapib and dalcetrapib have raised doubts re: the with torcetrapib and dalcetrapib have raised doubts re: the value of raising HDL-Cvalue of raising HDL-C
Still, Still, The one best study of niacin effects on CVD (HPS-2/THRIVE) The one best study of niacin effects on CVD (HPS-2/THRIVE)
is ongoing—results early in 2013is ongoing—results early in 2013 Investigational CETP inhibitors greatly increase HDL-C and Investigational CETP inhibitors greatly increase HDL-C and
might be shown to reduce CVD—clinical trials ongoing, results might be shown to reduce CVD—clinical trials ongoing, results after 2017after 2017
HDL-C Risk Factor vs Risk Marker?HDL-C Risk Factor vs Risk Marker?
Low HDL-C predicts high CVD RiskLow HDL-C predicts high CVD RiskHigh HDL-C predicts anti-atherogenic effects:High HDL-C predicts anti-atherogenic effects:
Anti-inflammatoryAnti-inflammatory AntioxidantAntioxidant AntithromboticAntithrombotic Pro-endothelialPro-endothelial
But clinical trials of HDL-C-raising agents so far But clinical trials of HDL-C-raising agents so far have failed to prove CVD benefit—suggesting have failed to prove CVD benefit—suggesting that HDL-C may be only a risk markerthat HDL-C may be only a risk marker
• Smoking Cessation− HDL-C levels are lower in smokers (by 7%-20%), and return
towards normal 1-2 months after smoking cessation• Whole Food Plant Based Diet—dietary fiber blunts adverse
carb effect• Weight Reduction
− For every 3 kg (7 lb) of weight loss, HDL-C levels increase by 2-4%, but only after stabilization at new lower weight
• Exercise− Aerobic exercise (40 min, 3-4 x weekly) may increase HDL-
C by 5-10%Rössner S et al. Atherosclerosis. 1987;64:125-130.Wood PD et al. N Engl J Med. 1988;319:1173-1179.Ornish D et al. JAMA. 1998;280:2001-2007.
Lifestyle Modifications to Raise HDL-C Lifestyle Modifications to Raise HDL-C LevelsLevels
Cullen P et al. Eur Heart J. 1998;19:1632-1641.Kokkinos PF et al. Arch Intern Med. 1995;155:415-420.Kodama S et al. Arch Intern Med. 2007;167:999-1008.
Available Agents for HDL-C RaisingAvailable Agents for HDL-C Raising
AgentAgent HDL-CHDL-C ↑↑ Primary UsePrimary Use
Nicotinic acidNicotinic acid 15-35%15-35% HDL HDL ↑↑
FibratesFibrates 5-20% 5-20% TG ↓ TG ↓
StatinsStatins 5-15% 5-15% LDL ↓ LDL ↓
Prescr. Om-3*Prescr. Om-3* 2-10% 2-10% TG ↓TG ↓
Bile-acid resins*Bile-acid resins* 2-5% 2-5% LDL ↓LDL ↓
Ezetimibe*Ezetimibe* 1-3% 1-3% LDL ↓LDL ↓
Pioglitazone*Pioglitazone* 5-20% 5-20% Glucose ↓Glucose ↓
Estrogens*Estrogens* 10-25% 10-25% Hot flashesHot flashes
-blockers*-blockers* 10-20% 10-20% BPHBPH
Alcohol*Alcohol* 5-15% 5-15% Social, etc.Social, etc.
*Lacking FDA-approved indication for HDL-raising.Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41:151-174.Insull W et al. Mayo Clin Proc. 2001;76:971-982.McKenney JM et al. Pharmacother. 2007;27:715-728.
Risk Reduction for CHD EventsRisk Reduction for CHD EventsAs a Function of Changes in TC, LDL-C, and As a Function of Changes in TC, LDL-C, and
HDL-CHDL-C
*4S, CARE, LIPID, WOSCOPS**HELSINKI, VA-HIT,AFCAPS/TexCAPS
PERCENT CHD EVENTCHANGE RATE
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)
CH
D D
eath
or
Nonfa
tal M
I (%
)
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 years
A fibrate does not provide significant additional benefit* in diabetics
Source: Keech A et al. Lancet 2005;366:1849-61
*Unadjusted for concomitant statin use
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction
Fibrate Evidence:Fibrate Evidence:Primary PreventionPrimary Prevention
ACCORD Lipid Study Results ACCORD Lipid Study Results (NEJM 2010; 362: 1563-74)(NEJM 2010; 362: 1563-74)
5518 patients with type 2 DM treated with open 5518 patients with type 2 DM treated with open label simvastatin randomly assigned to label simvastatin randomly assigned to fenofibrate or placebo and followed for 4.7 years.fenofibrate or placebo and followed for 4.7 years.
Annual rate of primary outcome of nonfatal MI, Annual rate of primary outcome of nonfatal MI, stroke or CVD death 2.2% in fenofibrate group stroke or CVD death 2.2% in fenofibrate group vs. 1.6% in placebo group (HR=0.91, p=0.33).vs. 1.6% in placebo group (HR=0.91, p=0.33).
Pre-specified subgroup analyses showed Pre-specified subgroup analyses showed possible benefit in men vs. women and those possible benefit in men vs. women and those with high triglycerides and low HDL-C.with high triglycerides and low HDL-C.
Results support statin therapy alone to reduce Results support statin therapy alone to reduce CVD risk in high risk type 2 DM patients.CVD risk in high risk type 2 DM patients.
Fibrate Evidence:Fibrate Evidence:Primary and Secondary PreventionPrimary and Secondary Prevention
Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial5,518 diabetic patients on statin therapy randomized to fenofibrate (160 mg) or placebo for 4.7 years
On a background of statin therapy, a fibrate does not reduce CV events in diabetics
CV
death
, nonfa
tal st
roke
or
nonfa
tal M
I (%
/year)
Placebo
2.4
Fenofibrate
3
2
1
0
2.2
P=0.32
8% RRR
Source: ACCORD study group. NEJM 2010;Epub ahead of print
CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction
Is Niacin Useful in Low HDL-C?Is Niacin Useful in Low HDL-C?
HATS: Percent Change in StenosisHATS: Percent Change in Stenosis
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Ch
ang
e (%
)
*P = 0.16 for comparison with placebo; †P < 0.001; ‡P = 0.004.HATS = HDL-Atherosclerosis Treatment Study.
Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592.
Placebo Antioxidant Simvastatin/ Simvastatin /Vitamins* Niacin† Niacin/
Antioxidants‡
Simvastatin-niacin97%
All placebos
76%RR = 0.10P = 0.03
0 1 2 30
70
80
90
100
HATS = HDL-Atherosclerosis Treatment Study.Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592.
HATS: Patients Free of EventsHATS: Patients Free of Events
Pa
tie
nts
Fre
e o
f E
ven
ts (
%)
Years
StudyTreatme
ntn/N
Controln/N
Peto OR95% Cl
Peto OR 95% Cl
ARBITER-6-HALTS 2/187 9/176 0.25 (0.08,
0.84)
Guyton JR et al 1/676 1/272 0.35 (0.02, 7.56)
AFREGS 0/71 1/72 0.14 (0.00, 6.92)
ARBITER-2 2/87 2/80 0.92 (0.13, 6.65)
HATS 1/38 5/38 0.24 (0.05, 1.26)
UCSF_SCOR 0/48 1/49 0.14 (0.00, 6.96)
STOCKHOLM 72/279 100/276 0.61 (0.43, 0.88)
CLAS 1/94 5/94 0.25 (0.05, 1.29)
CDP 287/1119 839/2789 0.81 (0.69, 0.94)
Total Test for heterogeneity: P = 0.24, I2 = 23.0% Test for overall effect: P <0.0001
0.75 (0.65, 0.86)
Subtotal excluding CDP 0.53 (0.38, 0.73)
0.1 0.2 0.5 1 2 5 10Log scale
Meta-Analysis: Effects of Nicotinic AcidMeta-Analysis: Effects of Nicotinic AcidPre-AIM-HIGH Trials: Major Coronary EventsPre-AIM-HIGH Trials: Major Coronary Events
Many of these trials were tests of drug combinations that included niacin.Bruckert E et al. Atherosclerosis. 2010;210:353-361.
AIM-HIGHAIM-HIGHDesign Design
Purpose: “Rigorous test of the HDL hypothesis…” Purpose: “Rigorous test of the HDL hypothesis…” ((notnot designed to be a test of niacin) designed to be a test of niacin)
Subjects: n=3414 men/women (85%/15%) w/ prior CVD event Subjects: n=3414 men/women (85%/15%) w/ prior CVD event and HDL-C 35 (<42/53) LDL-C 74 (algorithm), TG 163 (100-and HDL-C 35 (<42/53) LDL-C 74 (algorithm), TG 163 (100-400) [median (range)] 400) [median (range)]
Randomized TherapyRandomized Therapy Extended-release niacin (1500-2000 mg hs) vsExtended-release niacin (1500-2000 mg hs) vs
““Placebo” (immediate-release niacin 100-150 mg hs)Placebo” (immediate-release niacin 100-150 mg hs)
Open-label titration/addition (keep LDL-C in 40-80 mg/dL)Open-label titration/addition (keep LDL-C in 40-80 mg/dL) Simvastatin 5-80 mg/dSimvastatin 5-80 mg/d
Ezetimibe 10 mg/d + extended release niacin (1500-2000 mg)Ezetimibe 10 mg/d + extended release niacin (1500-2000 mg)
AIM-HIGH Investigators. N Engl J Med. 2001;365:2255-267.AIM-HIGH Investigators. Am Heart J. 2011;161:471-477.e2.
Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.
AIM-HIGH — ResultsHDL-C at Baseline and Follow-up
1o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization
Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.
AIM-HIGH — ResultsPrimary Outcome
Fate of Niacin Beyond AIM-HIGH: HPS2-Fate of Niacin Beyond AIM-HIGH: HPS2-THRIVE : December 2012 UpdateTHRIVE : December 2012 Update
HPS2-THRIVE evaluated extended-release HPS2-THRIVE evaluated extended-release niacin/laropiprant plus statin therapy versus statin niacin/laropiprant plus statin therapy versus statin therapy alone in patients at high risk for therapy alone in patients at high risk for cardiovascular eventscardiovascular events
HPS2-THRIVE did not reach the primary endpoint HPS2-THRIVE did not reach the primary endpoint to reduce coronary deaths, non-fatal heart attacks, to reduce coronary deaths, non-fatal heart attacks, strokes, or revascularizationsstrokes, or revascularizations
This finding, supportive of AIM-HIGH, suggests This finding, supportive of AIM-HIGH, suggests that niacin may not provide additional benefit to that niacin may not provide additional benefit to reduce CVD risk when patients are well-treated with reduce CVD risk when patients are well-treated with statinsstatins
Emerging HDL-C TherapiesEmerging HDL-C Therapies
CETP AntagonismCETP Antagonism
Role of CETP in AtherosclerosisRole of CETP in Atherosclerosis
Human CETP deficiency is usually associated with marked ↑ in HDL-CHuman CETP deficiency is usually associated with marked ↑ in HDL-C CETP activity is inversely correlated with plasma HDL-CCETP activity is inversely correlated with plasma HDL-C Decreasing CETP activity has consistently inhibited atherosclerosis in Decreasing CETP activity has consistently inhibited atherosclerosis in
animal modelsanimal models
Barter PJ et al. Arterioscler Thromb Vasc Biol. 2003;23:160-167.Contacos C et al. Atherosclerosis. 1998;141:87-98. Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28:148-154.
LIVER PERIPHERAL TISSUE
CE
TG
Bile
Foamcells
RCT HDL
ABC-A1
VLDL LDL
PLASMA
LDL-R
ABC-G1
Free cholesterol
CETP
Athero-sclerosisLDL
CETP Inhibitors: 2 Down, 2 RemainCETP Inhibitors: 2 Down, 2 Remain
CETP
Evacetrapib
↑CVD (25%) but OK HDL
function(off-target eff.?)
*No ↓CVD,but OK HDL
function, +/- anti athero?
--------------------↑HDL-C----------------------~80% ~80% ~138% ~30%
Lipid Effects of CETP Lipid Effects of CETP Inhibitors/ModulatorsInhibitors/Modulators% Change from Baseline% Change from Baseline
CETP AgentDose
(mg/day)HDL-C
(%)LDL-C
(%)TG (%)
Torcetrapib 60 61 -24 -9
Anacetrapib 100 138 -40 -7
Evacetrapib 500 129 -36 -11
Dalcetrapib 600 31 -2 -3
Adapted from Cannon C et al. JAMA. 2011;306:2153-2155. Nicholls SJ et al. JAMA. 2011;306:2099-2109.
Is the toxicity of torcetrapib related to the mechanism or the molecule?
Atorvastatin only
Torcetrapib plus atorvastatin
0 90 180 270 360 450 540 630 720 810
Days After Randomization
Patie
nts
With
out E
vent
(%)
10098969492900
Barter PJ et al. N Engl J Med. 2007;357:2109-2122.
Torcetrapib: Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality Torcetrapib: Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality
HR = 1.25P = 0.0001
Torcetrapib Caused Off-target Torcetrapib Caused Off-target HyperaldosteronismHyperaldosteronism
Torcetrapib arm of ILLUMINATE trial showed significant:Torcetrapib arm of ILLUMINATE trial showed significant:11
↑ ↑ Systolic BSystolic Blood Pressure:lood Pressure: Mean ↑Mean ↑5.4 mmHg5.4 mmHg >15 mmHg >15 mmHg ↑ ↑ SBP: 19.5% torcetrapib arm (vs 9.4% placebo SBP: 19.5% torcetrapib arm (vs 9.4% placebo
arm, arm, PP<0.001)<0.001) ↓ ↓ serum potassiumserum potassium ↑ ↑ serum bicarbonateserum bicarbonate ↑ ↑ serum sodiumserum sodium ↑ ↑ serum aldosteroneserum aldosterone
Inverse relationship of CVD and on-Rx-HDL-C Inverse relationship of CVD and on-Rx-HDL-C preservedpreserved Conclusion: ↑ CVD Conclusion: ↑ CVD in ILLUMINATE likely due to off-target actions of in ILLUMINATE likely due to off-target actions of
torcetrapib, not related to CETP inhibitiontorcetrapib, not related to CETP inhibition1,21,2
1. Barter PJ et al. N Engl J Med. 2007;357:2109-2122.2. Rosenson RS. Curr Athero Rep. 2008;10:227-229.
dal-OUTCOMES Results: Isolated ↑HDL-C
LDL
Chol
este
rol
(mg/
dL)
HDL
Chol
este
rol
(mg/
dL)
Schwartz GG et al. N Engl J Med. 2012 Nov 5. [Epub ahead of print].
No. at riskPlacebo 7907 7685 7498 7272 6959 6436 3650Dalcetrapib 7910 7663 7402 7196 6871 6333 3599
No. at riskPlacebo 7907 7679 7473 7265 6947 6427 3640Dalcetrapib 7910 7657 7382 7191 6863 6324 3591
Months
dal-OUTCOMES Results: No ↓CVD
Schwartz GG et al. N Engl J Med. 2012 Nov 5. [Epub ahead of print].
Year
Cum
ulat
ive In
ciden
ce o
f Prim
ary
Out
com
e (%
of p
atie
nts)
No. at riskPlacebo 7933 7386 6551 1743Dalcetrapib 7938 7372 6495 1736
dal-OUTCOMES Results: HDL STILL Functional
Schwartz GG et al. N Engl J Med. 2012 Nov 5. [Epub ahead of print].
Change in HDL Cholesterol (mg/dL) from Baseline to Month 1, According to Quintile
Annu
alize
d Ev
ent R
ate
(%)
Revisiting the HDL HypothesisRevisiting the HDL HypothesisWhere do we go Next?Where do we go Next?
Residual CVD risk exists despite intense statin Residual CVD risk exists despite intense statin monotherapymonotherapy
Low HDL-C predicts high CVD risk; high HDL-C is Low HDL-C predicts high CVD risk; high HDL-C is protective protective
Existing HDL raising therapies have inconsistent effectsExisting HDL raising therapies have inconsistent effects Clinical trials have not yet answered the following:Clinical trials have not yet answered the following:
Is HDL a Is HDL a causal factorcausal factor or a or a biomarkerbiomarker of risk? of risk? Does raising HDL-C reduce CVD risk?Does raising HDL-C reduce CVD risk?
Investigational drugs to raise HDL-C and reduce CVD Investigational drugs to raise HDL-C and reduce CVD riskrisk
Continued need for multifactorial approaches to reduce Continued need for multifactorial approaches to reduce CVD riskCVD risk
Current Investigational Approaches to Current Investigational Approaches to Reduce Residual CVD Risk via Enhanced Reduce Residual CVD Risk via Enhanced
HDL, etc.HDL, etc. Additional CETP inhibitors: anacetrapib, evacetrapibAdditional CETP inhibitors: anacetrapib, evacetrapib
Apolipoprotein A1 (Apo A1) Milano; Apo A1 agonistApolipoprotein A1 (Apo A1) Milano; Apo A1 agonist
Delipidated HDL; rHDLDelipidated HDL; rHDL
Selective LXRSelective LXRβ (β (liver X receptor) agonist liver X receptor) agonist
DMHCA; GW 3965DMHCA; GW 3965
PPAR (peroxisome proliferator-activated receptor PPAR (peroxisome proliferator-activated receptor αα//γγ agonistagonist
aleglitazar, muraglitazar, tesaglitazaraleglitazar, muraglitazar, tesaglitazar
DPP-4 (dipeptidyl peptidase-4) antagonistDPP-4 (dipeptidyl peptidase-4) antagonist
alogliptin, linagliptin, saxagliptin, sitagliptinalogliptin, linagliptin, saxagliptin, sitagliptin
MTP (microsomal transport protein) antagonistMTP (microsomal transport protein) antagonist
Lp-PLALp-PLA22 and vascular disease and vascular disease
LpPLA2 Studies Collaboration (2010) Lancet 375; 1536-1544
Effects of Lp-PLA2 inhibition by darapladib in diabetic, hypercholesterolemic pigs
Wilensky et al (2008) Nature Medicine (in press)
Novel anti-atherosclerotic agentsDarapladib in animal models and clinical trials
STABILITY Stabilization of Atherosclerotic Plaque by Initiation of Darapladib TherapyEstimated enrolment 15,500• Darapladib vs placebo in well treated patients with CHD plus other risk.• 1ary endpoint major coronary event
SOLID – TIMI52 Stabilization of plaques using darapladib.• Incidence of major coronary events in patients with ACS•Darapladib 160 mg vs placebo started within 30 days of index ACS event.
NCEP ATP III: Evaluation—NCEP ATP III: Evaluation—Major Risk Factors for CADMajor Risk Factors for CAD
Age (men Age (men 45 y; women 45 y; women 55 y)55 y)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
Cigarette smokingCigarette smoking
Hypertension (BP Hypertension (BP 140/90 mm Hg or 140/90 mm Hg or antihypertensive medication)antihypertensive medication)
HDL-C <40 mg/dLHDL-C <40 mg/dL
Family history of premature CADFamily history of premature CAD <55 y in first-degree male relative<55 y in first-degree male relative <65 y in first-degree female relative<65 y in first-degree female relative
Revised ATP III (AHA/NHLBI) Metabolic Syndrome Revised ATP III (AHA/NHLBI) Metabolic Syndrome Definition 2005Definition 2005
*Diagnosis is established when 3 of these risk factors are present.†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡Some men develop metabolic risk factors when circumference is only marginally increased.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497; Updated AHA/NHLBI Statement Oct 18, 2005: Grundy et al. Circulation 2005; 112 (epub).
<40 mg/dL<40 mg/dL<50 mg/dL <50 mg/dL or Rx for or Rx for ↓ HDL↓ HDL
MenMenWomenWomen
>>102 cm (102 cm (>>40 in)40 in)>>88 cm (88 cm (>>35 in)35 in)
MenMenWomenWomen
100 mg/dL 100 mg/dL or Rx for or Rx for ↑ glucose↑ glucoseFasting glucoseFasting glucose130/130/85 mm Hg 85 mm Hg or on HTN Rxor on HTN RxBlood pressureBlood pressure
HDL-CHDL-C150 mg/dL 150 mg/dL or Rx for or Rx for ↑ TG↑ TGTGTG
Abdominal obesityAbdominal obesity†† (Waist circumference(Waist circumference‡‡))
Defining LevelDefining LevelRisk FactorRisk Factor
NCEP ATP III: EvaluationNCEP ATP III: Evaluation——Need for Framingham CalculationNeed for Framingham Calculation
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
NoNo>20%>20%CAD or CAD risk CAD or CAD risk equivalentequivalent
YesYes0%-10%0%-10%2 RF2 RF
NoNo<10%<10%1 RF1 RF
Need for Need for Framingham Framingham CalculationCalculation
10-Year Risk 10-Year Risk for CADfor CADRisk ProfileRisk Profile
YesYes10%-20%10%-20%
NCEP ATP III: Evaluation—NCEP ATP III: Evaluation—CAD Risk EquivalentsCAD Risk Equivalents
DiabetesDiabetes
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
Atherosclerotic diseaseAtherosclerotic disease Peripheral artery diseasePeripheral artery disease Abdominal aortic aneurysmAbdominal aortic aneurysm Symptomatic carotid artery diseaseSymptomatic carotid artery disease
CAD 10-year risk >20%CAD 10-year risk >20%
Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Assessing CHD Risk in MenAssessing CHD Risk in MenStep 1: Age
YearsPoints
20-34 -935-39 -440-44 045-49 350-54 655-59 860-64 1065-69 1170-74 1275-79 13
Step 2: Total CholesterolTC Points at Points at Points at Points at
Points at(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
1280 11 8 5 3
1
HDL-C(mg/dL) Points
60 -1
50-59 0
40-49 1
<40 2
Step 3: HDL-Cholesterol
Systolic BP PointsPoints
(mm Hg) if Untreated if Treated
<120 0 0120-129 0 1130-139 1 2140-159 1 2160 2 3
Step 4: Systolic Blood Pressure
Step 5: Smoking Status
Points at Points at Points at Points atPoints at
Age 20-39 Age 40-49 Age 50-59 Age 60-69Age 70-79
Nonsmoker 0 0 0 00
Smoker 8 5 3 11
Age
Total cholesterol
HDL-cholesterol
Systolic blood pressure
Smoking status
Point total
Step 6: Adding Up the Points
Point Total 10-Year Risk Point Total 10-Year Risk
<0 <1% 118%
0 1% 1210%
1 1% 1312%
2 1% 1416%
3 1% 1520%
4 1% 1625%
5 2% 1730%
6 2%7 3%8 4%9 5%
10 6%
Step 7: CHD Risk
ATP III Framingham Risk Scoring
© 2001, Professional Postgraduate Services®
www.lipidhealth.org
Point Total 10-Year Risk Point Total 10-Year Risk
<9 <1% 2011%
9 1% 2114%
10 1% 2217%
11 1% 2322%
12 1% 2427%
13 2% 25 30%
14 2%15 3%16 4%17 5%18 6%19 8%
Assessing CHD Risk in WomenAssessing CHD Risk in Women
Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Step 1: Age
YearsPoints
20-34 -735-39 -340-44 045-49 350-54 655-59 860-64 1065-69 1270-74 1475-79 16
TC Points at Points at Points at Points atPoints at(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
2280 13 10 7 4
2
HDL-C(mg/dL) Points
60 -1
50-59 0
40-49 1
<40 2
Step 3: HDL-Cholesterol
Systolic BP PointsPoints
(mm Hg) if Untreated if Treated
<120 0 0120-129 1 3130-139 2 4140-159 3 5160 4 6
Step 4: Systolic Blood Pressure
Step 5: Smoking Status
Points at Points at Points at Points atPoints at
Age 20-39 Age 40-49 Age 50-59 Age 60-69Age 70-79
Nonsmoker 0 0 0 00
Smoker 9 7 4 21
Age
Total cholesterol
HDL-cholesterol
Systolic blood pressure
Smoking status
Point total
Step 6: Adding Up the Points
Step 7: CHD Risk
Step 2: Total Cholesterol
ATP III Framingham Risk Scoring
© 2001, Professional Postgraduate Services®
www.lipidhealth.org
hs-CRP Adds to Predictive Value of TC:HDL Ratio in hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MIDetermining Risk of First MI
0.0
1.0
2.0
3.0
4.0
5.0
High Medium Low Low
Medium
High
Total Cholesterol:HDL RatioTotal Cholesterol:HDL Ratio
Ridker et al, Circulation. 1998;97:2007–2011.
hs-CRP
hs-CRP
Rel
ativ
e R
isk
Rel
ativ
e R
isk
JUPITERWhy Consider Statins for Low LDL, high hsCRP Patients?
However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses.
Ridker et al, New Engl J Med 2001;344:1959-65
Low LDL, Low hsCRP
Low LDL, High hsCRP
Statin Effective Statin Not Effective
1.0 2.00.5
[A]
[B]
Low LDL, Low hsCRP
Low LDL, High hsCRP
Statin Effective Statin Not Effective
1.0 2.00.5
AFCAPS/TexCAPS Low LDL Subgroups
RR
Rosuvastatin 20 mg (N=8901)Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke
UnstableUnstable AnginaAngina
CVD DeathCVD DeathCABG/PTCACABG/PTCA
JUPITERJUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of Multi-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular EventsRosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRPAmong Individuals With Low LDL and Elevated hsCRP
4-week 4-week run-inrun-in
Ridker et al, Circulation 2003;108:2292-2297.
No Prior CVD or DMNo Prior CVD or DMMen Men >>50, Women 50, Women >>6060
LDL <130 mg/dL hsCRP >2 mg/L
JUPITERTrial Design
Placebo (N=8901)Placebo (N=8901)
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 / 8901
Rosuvastatin 142 / 8901
HR 0.56, 95% CI 0.46-0.69P < 0.00001
Number Needed to Treat (NNT5) = 25
- 44 %
0 1 2 3 4
0.0
00
.02
0.0
40
.06
0.0
8
Cu
mu
lati
ve In
cid
ence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
Ridker et al NEJM 2008
JUPITER population – high CRP (>2mg/l), low LDLDual Target Analysis: LDL-C <70 mg/dL, hsCRP <2 mg/L
LDL >70 mg/dLand / or
hsCRP >2 mg/LHR 0.64 (0.49-0.84)
LDL <70 mg/dL and hsCRP <2 mg/LHR 0.35 (0.23-0.54)
placebo HR 1.0 (referent)
P <0.0001
0 1 2 3 40.00
0.02
0.04
0.06
0.08
Cu
mu
lati
ve I
nci
den
ce
Number at RiskFollow-up (years)
rosuvastatinplacebo
7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 1457,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168
Ridker PM et al. Lancet 2009;373:1175–1182
1 RF
2 RFs
equivalent
CAD or CAD risk
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
Risk Category
<160
<130
<100
<130
LDL-C Goal
(mg/dL)
160
130
100
130
LDL-C Level to Initiate
TLC (mg/dL)
LDL-C Level to Initiate
Drug Therapy(mg/dL)
190
160
130
130
(10-year risk0%-10%)
(10-year risk10%-20%)
NCEP ATP III Guidelines: TreatmentNCEP ATP III Guidelines: Treatment
Statins in ACS - GuidelinesStatins in ACS - Guidelines
• Who - Initiate therapy regardless of baseline LDL.
• When – Pre-discharge; but no difference in benefit
when initiated immediately or days post event (ESC
<4 days).
• What – Evidence base is for high dose statin (but
not 80mg simvastatin).
• Goal - <70 mg/dl (2.0 mmol/l) LDL cholesterol.
ACC/ AHA 2007 in JACC (2008) 51; 210-47ESC 2007 in Eur Heart J (2007) 28; 1598-1660
Lipid Management Goal: Persons Lipid Management Goal: Persons with Pre-existing CHDwith Pre-existing CHD
LDL-C should be less than 100 mg/dL
Further reduction to LDL-C to < 70 mg/dL is reasonable
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
*Non-HDL-C = total cholesterol minus HDL-C
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL*
1 RF <190
2 RFs(CAD risk 20%) <160
CAD or CAD risk equivalent <130
(CAD risk >20%)
NCEP ATP III: Setting Goals—NCEP ATP III: Setting Goals—SecondarySecondary––Non-HDL-CNon-HDL-C
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
Risk Category Non–HDL-C Goal (mg/dL)
(Patients With TG (Patients With TG 200)200)
Level Level (mg/dl)(mg/dl)
ClassificationClassification
<200<200 DesirableDesirable
200-239200-239 Borderline HighBorderline High
>>240240 HighHigh
Level Level (mg/dl)(mg/dl)
ClassificationClassification
>40>40 Minimum goal*Minimum goal*
40-5040-50 Desired goal*Desired goal*
>50>50 HighHigh
Level Level (mg/dl)(mg/dl)
ClassificationClassification
<150<150 NormalNormal
150-199150-199 Borderline HighBorderline High
200-499200-499 HighHigh
>>500500 Very HighVery High
Total Cholesterol HDL-Cholesterol
Triglyceride
Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-97
ATP III Classification of Other Lipoprotein ATP III Classification of Other Lipoprotein LevelsLevels
*These goals apply to men. For women, the minimum goal is >50 mg/dL
HDL=High density lipoprotein
NCEP ATP III Guidelines: TreatmentNCEP ATP III Guidelines: Treatment
TherapeuticLifestyle Change (TLC)
Improve diet
Weight reduction
Physical activity
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
PharmacologicTreatment
Statins (HMG-CoA reductase inhibitors)
Fibrates
Niacin
Bile acid sequestrants
Lipid Management Lipid Management RecommendationsRecommendations
Start dietary therapy (<7% of total calories as saturated fat and <200 mg/d cholesterol)
Adding plant stanol/sterols (2 gm/day) and viscous fiber (>10 mg/day) will further lower LDL
Promote daily physical activity and weight management.
Encourage increased consumption of omega-3 fatty acids in fish or 1 g/day omega-3 fatty acids in capsule form for risk reduction.
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
For all patients
Therapeutic Lifestyle ChangesTherapeutic Lifestyle ChangesNutrient Composition of TLC DietNutrient Composition of TLC Diet
NutrientNutrient Recommended IntakeRecommended Intake
Saturated fatSaturated fat Less than 7% of total calories Less than 7% of total calories
Polyunsaturated fatPolyunsaturated fat Up to 10% of total caloriesUp to 10% of total calories
Monounsaturated fat Monounsaturated fat Up to 20% of total calories Up to 20% of total calories
Total fatTotal fat 25–35% of total calories25–35% of total calories
CarbohydrateCarbohydrate 50–60% of total calories50–60% of total calories
FiberFiber 20–30 grams per day20–30 grams per day
ProteinProtein Approximately 15% of total calories Approximately 15% of total calories
CholesterolCholesterol Less than 200 mg/dayLess than 200 mg/day
Total calories (energy)Total calories (energy) Balance energy intake and expenditure Balance energy intake and expenditure to maintain desirable body weightto maintain desirable body weight
Possible Benefits From Other TherapiesPossible Benefits From Other Therapies
Therapy Result
• Soluble fiber in diet (2–8 g/d) (oat bran, fruit, and vegetables)
• Soy protein (20–30 g/d)
• Stanol esters (1.5–4 g/d) (inhibit cholesterol absorption)
• Fish oils (3–9 g/d) (n-3 fatty acids)
LDL-C 1% to 10%
LDL-C 5% to 7%
LDL-C 10% to 15%
Triglycerides 25% to 35%
Jones PJ. Curr Atheroscler Rep. 1999;1:230-235.Lichtenstein AH. Curr Atheroscler Rep. 1999;1:210-214.Rambjor GS et al. Lipids. 1996;31:S45-S49.Ripsin CM et al. JAMA. 1992;267:3317-3325.
Dietary AdjunctsDietary Adjuncts
TLC for patients with LDL-C = 160TLC for patients with LDL-C = 160
Walden CE et al. Arterioscler Thromb Vasc Biol 1997;17:375-382.Jenkins DJ et al. Curr Opin Lipidol 2000;11:49-56.Cato N. Stanol meta-analysis. Personal communication, 2000.
Dietary ComponentDietary Component LDL-C LDL-C (mg/dL) (mg/dL)
Low saturated fat/dietary cholesterolLow saturated fat/dietary cholesterol ––1212
Viscous fiber (10–25 g/d)Viscous fiber (10–25 g/d) – –88
Plant stanols/sterols (2 g/d)Plant stanols/sterols (2 g/d) ––1616
TotalTotal – –36 mg/dl36 mg/dl
Moderate physical activity at least 30-60 minutes 5 days a week or longer will help to raise HDL-C, lower total and LDL-C, lower TG, lower glucose, insulin, and blood pressure levels.
Questran® Prescribing Information, Colestid ® Prescribing Information, WelChol ® Prescribing information, Niaspan ® Prescribing Information, Lopid ® Prescribing Information, TriCor ® Prescribing Information, Lipitor ® Prescribing Information, Zocor ® Prescribing Information, Mevaco ® r Prescribing Information, Lescol ® Prescribing Information, Pravacol ® Prescribing Information; Zetia ® Prescribing Information.
Effect of Lipid-modifying Therapies
TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin.
TherapyTherapy TCTC LDLLDL HDLHDL TGTG Patient Patient tolerabilitytolerability
Bile acid Bile acid sequestrantssequestrants
7-10%7-10% 10-18%10-18% 3%3% Neutral or Neutral or PoorPoor
Nicotinic acidNicotinic acid 10-20%10-20% 10-20%10-20% 14-35%14-35% 30-70%30-70% Poor to Poor to reasonablereasonable
Fibrates Fibrates (gemfibrozil)(gemfibrozil)
19%19% 4-21%4-21% 11-13%11-13% 30%30% GoodGood
Statins*Statins* 19-37%19-37% 25-50%25-50% 4-12%4-12% 14-29%14-29% GoodGood
EzetimibeEzetimibe 13%13% 18%18% 1%1% 9%9% GoodGood
When LDL-lowering drug therapy When LDL-lowering drug therapy
is employed in high-risk or is employed in high-risk or
moderately high risk patients, moderately high risk patients,
intensity of therapy should be intensity of therapy should be
sufficient to achieve a 30–40% sufficient to achieve a 30–40%
reduction in LDL-C levels.reduction in LDL-C levels.
Effect of Statin Therapy on LDL-C Effect of Statin Therapy on LDL-C Levels: “The Rule of 6”Levels: “The Rule of 6”
Illingworth 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 (%)
Starting dose LDL-C
Highestrecommended dose
AtorvastatinAtorvastatin
PravastatinPravastatin
RosuvastatinRosuvastatin
SimvastatinSimvastatin
10 mg10 mg 20 mg20 mg 40 mg40 mg 80 mg80 mg
DoseDose
*P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg**P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg† P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg1.Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160. 2.Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.
*P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg**P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg† P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg1.Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160. 2.Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.
*
**†
–60–60
–50–50
–40–40
–30–30
–20–20
–10–10
00
Mean
Perc
en
t C
han
ge F
rom
B
ase
line in
LD
L-C
(
SE
)M
ean
Perc
en
t C
han
ge F
rom
B
ase
line in
LD
L-C
(
SE
)Percentage Change From Baseline in Percentage Change From Baseline in
LDL-C at Week 6 by Dose (ITT)LDL-C at Week 6 by Dose (ITT)1,21,2
Grundy et al. Circulation. 2004;110:227-239.
Doses of Statins Required to Attain 30-40% Reduction of LDL-C
Dose, mg/dDose, mg/d LDL Reduction, LDL Reduction, %%
AtorvastatinAtorvastatin 1010 3939
Lovastatin Lovastatin 4040 3131
Pravastatin Pravastatin 4040 3434
Simvastatin Simvastatin 20-4020-40 35-4135-41
Fluvastatin Fluvastatin 40-8040-80 25-3525-35
Rosuvastatin 5-10 39-45
Source: Kashani A et al. Circulation 2006;114:2788-97
• 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)
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.
HMG-CoA Reductase Inhibitor:HMG-CoA Reductase Inhibitor:Adverse EffectsAdverse Effects
Hepatocyte
Skeletal myocyte
Why combination therapy?Why combination therapy?
Few patients achieve LDL-C goal on Few patients achieve LDL-C goal on monotherapymonotherapy
Uptitration of dosage is rareUptitration of dosage is rare
LDL-C goals are getting more aggressiveLDL-C goals are getting more aggressive
High-dose statins increase risk of side effectsHigh-dose statins increase risk of side effects
Can address mixed dyslipidemia (e.g., few pts Can address mixed dyslipidemia (e.g., few pts achieve adequate control of HDL-C and achieve adequate control of HDL-C and triglycerides on monotherapy)triglycerides on monotherapy)
Options for Patients who Fail to Reach Options for Patients who Fail to Reach LDL-C Goal on Statin MonotherapyLDL-C Goal on Statin Monotherapy
• Niacin• Bile acid sequestrant• Cholesterol absorption inhibitor
Addition of:Addition of:
Pharmacologic Therapy: NiacinPharmacologic Therapy: Niacin
Reduces HDL catabolism and VLDL productionReduces HDL catabolism and VLDL production
Primarily used to treat low HDL-C (15%-35%Primarily used to treat low HDL-C (15%-35%) ) and elevated TG (20%-50% and elevated TG (20%-50% ))
LDL-C LDL-C 5%-25% 5%-25%
Side effectsSide effects Hepatotoxicity, hyperglycemia, hyperuricemia,Hepatotoxicity, hyperglycemia, hyperuricemia,
upper GI distress, flushing, itchingupper GI distress, flushing, itching
Contraindicated in patients with liver disease,Contraindicated in patients with liver disease,gout, peptic ulcergout, peptic ulcer
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
Mean c
hang
e f
rom
Base
line
Source: 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%
1000 1500 2000 2500Dose (mg) 3000
Nicotinic Acid Evidence:Nicotinic Acid Evidence:Effect on Lipid ParametersEffect on Lipid Parameters
-50
-40
-30
-20
-10
0
10
20
30
HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride
Bile Acid SequestrantsBile Acid Sequestrants
Major actionsMajor actions Reduce LDL-C 15%-30%Reduce LDL-C 15%-30% Raise HDL-C 3%Raise HDL-C 3%-5%-5% May increase TGMay increase TG
Side effectsSide effects GI distress/constipationGI distress/constipation Decreased absorption of other drugs (1st generation)Decreased absorption of other drugs (1st generation)
ContraindicationsContraindications DysbetalipoproteinemiaDysbetalipoproteinemia Elevated TG (especially >400 mg/dL)Elevated TG (especially >400 mg/dL)
New Bile Acid SequestrantNew Bile Acid Sequestrant: : ColesevelamColesevelam
Lower dose for effectLower dose for effect
Fewer GI complaints than with other bileFewer GI complaints than with other bileacid sequestrantsacid sequestrants
Reduces absorption of Reduces absorption of -carotene-carotene
Requires 4-6 tablets/dayRequires 4-6 tablets/day
Davidson et al. Expert Opin Investig Drugs. 2000;9:2663.
Insull et al. Mayo Clin Proc. 2001;76:971.
*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
han
ge
fro
m b
asel
ine
at w
k 24
TGHDL-CLDL-C
*
†
Placebo (n=88)
Colesevelam 3.8 g/d (n=95)
Colesevelam Monotherapy: EfficacyColesevelam Monotherapy: Efficacy
Pharmacologic Therapy: FibratesPharmacologic Therapy: Fibrates
Inhibit hepatic TG production and increase HDL productionInhibit hepatic TG production and increase HDL production
Used to treat elevated TG (20%-50% Used to treat elevated TG (20%-50% ) ) and low HDL-C (10%-20% and low HDL-C (10%-20% ))
Variable effect on LDL-CVariable effect on LDL-C
Side effectsSide effects Dyspepsia, gallstones, myopathyDyspepsia, gallstones, myopathy Increased with statinsIncreased with statins
Contraindicated in patients with severe renal or hepatic Contraindicated in patients with severe renal or hepatic diseasedisease
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
Limitations of Current Limitations of Current Intestinal-Acting AgentsIntestinal-Acting Agents
Bile acid sequestrantsBile acid sequestrants NoncomplianceNoncompliance GI tolerabilityGI tolerability Reduced absorption of lipid-soluble vitaminsReduced absorption of lipid-soluble vitamins May increase TG in patients with hypertriglyceridemiaMay increase TG in patients with hypertriglyceridemia
Plant stanol and sterol estersPlant stanol and sterol esters Lack of selectivityLack of selectivity Some patients may find difficult to incorporate into Some patients may find difficult to incorporate into
dietdiet May reduce absorption of lipid-soluble vitaminsMay reduce absorption of lipid-soluble vitamins
Ezetimibe — Ezetimibe — Localizes at Brush Border of Small IntestineLocalizes at Brush Border of Small Intestine
Ezetimibe, a selective cholesterol absorption Ezetimibe, a selective cholesterol absorption inhibitor, localizes and appears to act at the inhibitor, localizes and appears to act at the brush border of the small intestine and inhibits brush border of the small intestine and inhibits cholesterol absorptioncholesterol absorption
This results inThis results in A decrease in the delivery of intestinal cholesterol to A decrease in the delivery of intestinal cholesterol to
the liverthe liver A reduction of hepatic cholesterol stores and an A reduction of hepatic cholesterol stores and an
increase in clearance of cholesterol from the bloodincrease in clearance of cholesterol from the blood
Ezetimibe and StatinsEzetimibe and StatinsComplementary MechanismsComplementary Mechanisms
Ezetimibe reduces the delivery of cholesterol to the liverEzetimibe reduces the delivery of cholesterol to the liver
Statins reduce cholesterol synthesis in the liverStatins reduce cholesterol synthesis in the liver
The distinct mechanism of ezetimibe is complementary to The distinct mechanism of ezetimibe is complementary to that of statinsthat of statins
The effects of ezetimibe, either alone or in addition to a The effects of ezetimibe, either alone or in addition to a statin, on cardiovascular morbidity or mortality have not statin, on cardiovascular morbidity or mortality have not been establishedbeen established
Knopp RH. N Engl J Med. 1999;341:498–511.
Mea
n P
erce
nt
Ch
ang
e in
L
DL
-C F
rom
Bas
elin
e
Placebo(n = 11)
-30
-20
-10
0
SIMVA 10 mg(n = 12)
SIMVA 10+EZE 10 mg
(n = 11)
-34.9*
-51.9*†
-3.2
-40
-50
-60
Coadministration:Simvastatin + Ezetimibe
*P < 0.01 vs placebo
†P < 0.01 vs simvastatin 10 mg
Stein, E. Eur Heart J. 2001;3(suppl E):E14.
17%
% R
ed
uct
ion
Triglyceride
*P<0.05
-10 -20 -30 -40 -50
0
-46*
-21*
Total Cholesterol
Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731
27 patients with hypertriglyceridemia and low HDL-C treated with -3 fatty acid (4 grams/day) for 7 months
-3 Fatty Acids Evidence:-3 Fatty Acids Evidence:Effect on Lipid ParametersEffect on Lipid Parameters
HDL-C=High-density lipoprotein cholesterol
Source: Yokoyama M et al. Lancet. 2007;369:1090-8
Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS)
*Composite of cardiac death, myocardial infarction, angina, PCI, or CABG
Years
-3 Fatty Acids Evidence:-3 Fatty Acids Evidence:Primary and Secondary PreventionPrimary and Secondary Prevention
18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a statin or a statin alone for 5 years
-3 fatty acids provide CV benefit, particularly in secondary prevention CV=Cardiovascular, EPA=Eicosapentaenoic acid
-3 Fatty Acids -3 Fatty Acids Evidence:Evidence:Secondary Secondary PreventionPrevention
**p<0.05
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
7.0%
8.0%
-3 Fatty Acids
Placebo
Source: Burr ML et al. Lancet 1989;2:757-761
Diet and Reinfarction Trial (DART)
All
cause
mort
alit
y
(%)
*Corresponds to 2.5 grams of EPA (PUFA)
EPA=Eicosapentaenoic acid, MI=Myocardial infarction
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
-3 fatty acids reduce all cause mortality** after a MI
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
-3 fatty acids provide significant CV benefit after a MI
Source: GISSI Investigators. Lancet 1999;354:447-455
-3 Fatty Acids -3 Fatty Acids Evidence:Evidence:Secondary Secondary PreventionPreventionGruppo Italiano per lo Studio della Sopravvivenza
nell’Infarto miocardico (GISSI-Prevenzione)
CV=Cardiovascular, MI=Myocardial infarction, NF=Non-fatal, PUFA=Polyunsaturated fatty acids
Perc
ent
of
pati
ents P=0.04
8P=0.053 P=0.023 P=0.00
8
stroke stroke
02468
10121416
Death,NF MI,
NF stroke(2 way)
CVdeath,NF MI,and NF
Death,NF MI,
NF stroke(4 way)
CVdeath,NF MI,and NF
-3 PUFAPlacebo
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
-3 fatty acids provide no benefit following a MI in those with high utilization of risk reducing therapies
OMEGA Trial
Source: Senges J et al. Presented at the Annual Scientific Sessions of the American College of Cardiology, March 2009, Orlando, FL
Placebo
8.8
Fatty acids
12
8
4
0
10.4
P=0.10
Rate
of
rein
farc
tion,
stro
ke, or
death
* (%
)
DHA=Docosahexaenoic acid, EPA=Eicosapentaenoic acid, MI=Myocardial infarction
*This is a secondary endpoint
-3 Fatty Acids Evidence:-3 Fatty Acids Evidence:Secondary PreventionSecondary Prevention
CONCLUSIONSCONCLUSIONS
Many persons with normal total or LDL-C levels still Many persons with normal total or LDL-C levels still suffer CHD events.suffer CHD events.
While statin-based clinical trials significantly reduce risk While statin-based clinical trials significantly reduce risk of CHD, residual risk still exists.of CHD, residual risk still exists.
Non-HDL-C, which reflects all the atherogenic lipid Non-HDL-C, which reflects all the atherogenic lipid fractions, appears to be a stronger predictor of CHD fractions, appears to be a stronger predictor of CHD events than LDL-C.events than LDL-C.
The measurement of non-HDL-C and its use as a The measurement of non-HDL-C and its use as a secondary therapeutic target is warranted to better secondary therapeutic target is warranted to better address residual CHD risk. address residual CHD risk.
Lifestyle therapies as well as pharmacologic approaches, Lifestyle therapies as well as pharmacologic approaches, particular combination therapy with statins and other particular combination therapy with statins and other agents, are important for optimizing the entire lipid agents, are important for optimizing the entire lipid profile.profile.