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 Heart Disease Prevention ProgramProgram
Division of CardiologyDivision of Cardiology
University of California, IrvineUniversity of California, Irvine
Learning ObjectivesLearning Objectives
Discuss the epidemiological evidence for a role of Discuss the epidemiological evidence for a role of cholesterol and lipoproteins in coronary heart diseasecholesterol and lipoproteins in coronary heart disease
Examine the results of important cholesterol lowering Examine the results of important cholesterol lowering clinical trials and understand their relevance in clinical clinical trials and understand their relevance in clinical practicepractice
Review current NCEP goals for lipid managementReview current NCEP goals for lipid management
Evaluate the efficacy and safety profiles of various Evaluate the efficacy and safety profiles of various cholesterol lowering strategies including diet and lifestyle cholesterol lowering strategies including diet and lifestyle regimens and pharmacologic agentsregimens and pharmacologic agents
LipoproteinsLipoproteins
Water-soluble way to transport hydrophobic lipidsWater-soluble way to transport hydrophobic lipids
• Envelope of phospholipids and free cholesterol
• Triglyceride and cholesteryl ester-rich core
• Vary in size and density
From: Braunwald et al, Heart Disease: A Textbook of Cardiovascular Medicine 6 th ed., 2001
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 thes e lipoprote in partic les .found in plaque at biops y
1.050
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
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
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
Source: NHANES IV 2003-2004 data, US population projected to 2007. N = 212 million
Low HDL-C (26%, 54.7 M)Men: HDL < 40 mg/dl
Women: HDL < 50 mg/dl
High TG (13%, 27.5 M)TG ≥ 200 mg/dl
High LDL-C (28%, 59.7 M)≥2RF and FRS >20, CVD, DM or CKD: LDL ≥ 100 mg/dL
≥2RF and FRS ≤20: LDL ≥ 130 mg/dl<2RF: LDL ≥ 160 mg/dL
3% (6.8 M)
4% (7.6 M)
3% (6.2 M)
6% (13.7 M)
13% (26.6 M)
3% (6.9 M)
16% (33.0 M)
Overall U.S. Adult Population
No Lipid Disorder52%, 111.1 M
Ghandehari and Wong et al., Am Heart J 2008
Low HDL-C (27%, 2.1 M)Men: HDL < 40 mg/dl
Women: HDL < 50 mg/dl
High TG (27%, 2.2 M)TG ≥ 200 mg/dl
High LDL-C (60%, 4.7 M)LDL ≥ 100 mg/dL
10% (0.76 M)
5% (0.38 M)
10% (0.81 M)
5% (0.41 M)
7% (0.56 M)
3% (0.23 M)
35%(2.8 M)
Overall Coronary Heart Disease Subpopulation
No Lipid Disorder26%, 2.1 M
Source: NHANES IV 2003-2004 data, US population projected to 2007. N = 8 million
Treatment Rates among U.S. Adults with Treatment Rates among U.S. Adults with Dyslipidemia in 2003-2004 Dyslipidemia in 2003-2004
(Ghandehari and Wong et al., Am Heart J 2008)(Ghandehari and Wong et al., Am Heart J 2008)
Overall 35%, Men 36%, Women 34%Overall 35%, Men 36%, Women 34%
Non-Hispanic Whites 36%, Blacks 26%, Non-Hispanic Whites 36%, Blacks 26%, Hispanic 28%Hispanic 28%
No Disease 24%, CHD 63%, Stroke 36%, No Disease 24%, CHD 63%, Stroke 36%, Diabetes 48%Diabetes 48%
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 40–4950–59 ≥ 60< 200
230–259200–229
≥ 260
HDL-C (mg/dL) Tota
l-C (m
g/dL
)
14-y
inci
den
ce
rate
s (%
) fo
r CH
D
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
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
LDL Particle Size Subclass: LDL Particle Size Subclass:
Fasting triglycerides of 175 mg/dl or greater or TG/HDL Fasting triglycerides of 175 mg/dl or greater or TG/HDL ratio >3 is a good surrogate of small, dense LDL ratio >3 is a good surrogate of small, dense LDL
particle sideparticle side
IDLIDL L3L3 L2L2 L1L1
large, large, buoyantbuoyant
small, densesmall, dense
AA BBABAB
Accumulation of Other Risk Factors Accumulation of Other Risk Factors Compound Effects of Dyslipidemia on Risk Compound Effects of Dyslipidemia on Risk
of CHDof CHD
0
5
10
15
20
25
30
35
40
185 210 235 260 285 310 335
Low HDL
Smoking
Hyperglycemia
Hypertension
No Other Risk Factors
Schaefer EJ, adapted from the Framingham Heart Study
CH
D R
isk
Per
100
0 (i
n 6
yea
rs)
Serum Cholesterol (mg/dL)
Adapted from Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q.
Primary and Secondary Prevention Trials With Statins
2° prevention placebo
2° prevention statin
1° prevention placebo
1° prevention statin
0
5
10
15
20
25
30
80 90 100 110 120 130 140 150 160 170 180 190 200
LDL-C Achieved (mg/dL)
AFCAPS
AFCAPS
WOSCOPS
WOSCOPS
CARECARE
LIPID LIPID
4S
4S
Eve
nt
Rat
e (%
)
HPSHPS
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
Statin Trials: Therapy Reduces Major Coronary Events in Women
n = number of women enrolled.* 4S = primarily CHD death and nonfatal MI;
CARE = coronary death, nonfatal MI, angioplasty, or bypass surgery;AFCAPS/TexCAPS = fatal/nonfatal MI, unstable angina, or sudden cardiac death.
Miettinen TA et al. Circulation. 1997;96:4211-4218.Lewis SJ et al. J Am Coll Cardiol. 1998;32:140-146.Downs JR et al. JAMA. 1998;279:1615-1622.
4S (n=827) CARE (n=576) AFCAPS/TexCAPS (n=997)
2° Prevention 1° Prevention
-50-45-40-35-30-25-20-15-10-505
10
Major coronary events*
-34
-46 -46
% ∆
P=0.012
P=0.001
-15
-32*
-27*
-40
-30
-20
-10
0
Crouse JR et al. Arch Intern Med. 1997;157:1305-1310.
*P=0.001.†95% confidence interval of percentage of relative reduction.
Effects of Statins on Stroke: A Meta-analysis of Effects of Statins on Stroke: A Meta-analysis of Primary- and Secondary-Prevention TrialsPrimary- and Secondary-Prevention Trials
Relativereductionin rates
(%)
1° Prevention (-42 to -27)†
2° Prevention (13-45)†
Combined (11-40)†
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 (0.67−0.79)P < 0.0001
0.76 (0.70−0.83)P < 0.0001
0.76 (0.72−0.81)P < 0.0001
Statin Better Placebo Better
Heart Protection Study Collaborative Group. Lancet. 2002;360:7−22.
HPS—Simvastatin: Vascular Events by Baseline LDL-C
358 (21.0%)282 (16.4%)<100
871 (24.7%)668 (18.9%)100–129
2585 (25.2%)2033 (19.8%)All patients
1356 (26.9%)1083 (21.6%)≥130
Placebo (n = 10,267)
Statin (n = 10,269)
Baseline
LDL-C (mg/dL)
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
Collaborative Atorvastatin Diabetes Collaborative Atorvastatin Diabetes Study (CARDS)Study (CARDS)
2838 patients aged 40-75 with type 2 diabetes, 2838 patients aged 40-75 with type 2 diabetes, no prior CVD, but at least 1 of the following: no prior CVD, but at least 1 of the following: retinopathy, albuminuria, smoking, or retinopathy, albuminuria, smoking, or hypertensionhypertension
Randomization to 10 mg atorvastatin or placeboRandomization to 10 mg atorvastatin or placebo
Mean follow-up 3.9 yearsMean follow-up 3.9 years
Reduction in all CVD events of 37% (p=0.001), Reduction in all CVD events of 37% (p=0.001), all cause mortality 27% (p=0.059). CHD events all cause mortality 27% (p=0.059). CHD events reduced 36% and stroke 48%.reduced 36% and stroke 48%.
Colhoun HM et al., The Lancet 2004; 364: 685-696
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
LaRosa JC et al. NEJM. 2005;352:1425-1435
LDL-C=Low density lipoprotein cholesterol; TNT=Treating to New Targets; HPS=Heart Protection Study; CARE=Cholesterol and Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study.
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)HPS
CARE
LIPIDLIPID
CAREHPS
Eve
nt (
%) 4S
4SStatinPlacebo
Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD
HMG-CoA Reductase Inhibitor: HMG-CoA Reductase Inhibitor: Secondary PreventionSecondary Prevention
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
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
0.150.15Atorvastatin 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
METEOR Trial: Study DesignMETEOR Trial: Study Design
● Primary Endpoint: Annualized rate of change in maximum CIMTPrimary Endpoint: Annualized rate of change in maximum CIMT● Secondary Endpoint: Annualized rate of change in maximum CIMT derived Secondary Endpoint: Annualized rate of change in maximum CIMT derived
from the near and far walls of the right and left common carotid artery; the from the near and far walls of the right and left common carotid artery; the right and left carotid bulb; the right and left internal carotid artery; and right and left carotid bulb; the right and left internal carotid artery; and annualized rate of change in mean CIMT for the near and far walls of the annualized rate of change in mean CIMT for the near and far walls of the right and left common carotid artery.right and left common carotid artery.
Rosuvastatin (Rosuvastatin (40mg)40mg)n=702n=702
PlaceboPlacebon=282n=282
984 asymptomatic patients with moderately elevated cholesterol and low risk of CVD984 asymptomatic patients with moderately elevated cholesterol and low risk of CVDaccording to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk according to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk
factor and LDL 120-190mg/dL or factor and LDL 120-190mg/dL or >> 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart disease risk < 10%); HDL-C disease risk < 10%); HDL-C <<60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the 60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the
extracranial carotid arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm) extracranial carotid arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm) 5:2 Randomized. Double-blinded. Placebo-controlled.5:2 Randomized. Double-blinded. Placebo-controlled.
Mean age = 57 years. 40% Female.Mean age = 57 years. 40% Female.
RR
6, 12, 18 and 24 mos. follow-up
ACC 2007
-0.0014
0.0131
-0.005
0.000
0.005
0.010
0.015• After two years, After two years,
treatment with treatment with rosuvastatin was rosuvastatin was associated with a associated with a statistically statistically significant reduction significant reduction in the rate of in the rate of progression of CIMT progression of CIMT thickening in overall thickening in overall carotid segments, carotid segments, while the placebo while the placebo group displayed group displayed progression progression (p<0.001).(p<0.001). C
hang
e in
CIM
T f
or
12 C
arot
id A
rter
y si
tes
(mm
/C
hang
e in
CIM
T f
or
12 C
arot
id A
rter
y si
tes
(mm
/ye
ar)
year
)METEOR Trial: Primary EndpointMETEOR Trial: Primary Endpoint
n = 702n = 702
n = 282n = 282
p < 0.001 p < 0.001
ACC 2007
Change in maximum CIMT with rosuvastatin vs. placeboChange in maximum CIMT with rosuvastatin vs. placebo
RosuvastatinRosuvastatin
PlaceboPlacebo
Are LDL and HDL Effects Additive?Are LDL and HDL Effects Additive?
R2 = 0.8512
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80
% Absolute Change in LDL+HDL
% C
V E
ven
t R
RR
HATS
FATS
FATS F/U
4SVA HIT DAIS
BIP
AFCAPS/TexCAPS
WOSCOPS
LIPIDCARE, HPS
HHS
CDP
ASCOT
ALLHAT
PROSPER
2nd Order Relationship
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 Events
Pat
ien
ts F
ree
of
Ev
ents
(%
)
Years
ARBITER 2: Primary Endpoint ARBITER 2: Primary Endpoint Carotid IMT Across 12 MonthsCarotid IMT Across 12 Months
∆ CIMT at 12 months
• Statin vs ER niacin + statin P = 0.08
• Intent-to-treat analysis of statin vs. ER niacin + statin P = 0.048
• Non-Insulin resistant pts only: statin vs. ER niacin P = 0.026
Taylor AJ, et al. ARBITER 2: A double-blind, placebo-controlled study of extended-release niacin on Atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Ch
ang
e in
CIM
T (
mm
+/-
SE
M)
ER Niacin Placebo
68% decrease in progression
ASTEROID Trial, ACC 2008ASTEROID Trial, ACC 2008
AA SStudy tudy tto o EEvaluate the Effect of valuate the Effect of RRosuvastatin osuvastatin oon n IIntravascular ntravascular UUltrasound-ltrasound-DDerived Coronary erived Coronary
Atheroma BurdenAtheroma Burden
Prior studies have shown evidence of a decrease Prior studies have shown evidence of a decrease in atherosclerosis progression with statin therapy.in atherosclerosis progression with statin therapy.
No statin monotherapy has demonstrated a No statin monotherapy has demonstrated a cessation or regression of atherosclerosis.cessation or regression of atherosclerosis.
ASTEROID Trial: Study DesignASTEROID Trial: Study Design
● Primary Endpoint: Rosuvastatin regression of coronary Primary Endpoint: Rosuvastatin regression of coronary atherosclerosis by intravascular ultrasound (IVUS)atherosclerosis by intravascular ultrasound (IVUS)
● Secondary Endpoint: Rosuvastatin regression of coronary Secondary Endpoint: Rosuvastatin regression of coronary atherosclerosis by quantitative coronary angiography atherosclerosis by quantitative coronary angiography (QCA).(QCA).
Rosuvastatin Rosuvastatin 40 mg/day40 mg/day
n=292n=292
507 patients 507 patients >> 18 years with angiographic evidence of CAD, excluding patients 18 years with angiographic evidence of CAD, excluding patients using lipid-lowering medication for more than 3 mos within the previous 12 using lipid-lowering medication for more than 3 mos within the previous 12
mos, uncontrolled triglyceride levels, and poorly controlled diabetes. mos, uncontrolled triglyceride levels, and poorly controlled diabetes. Prospective. Multicenter. International. Open Label. Treatment for 24 mos. Prospective. Multicenter. International. Open Label. Treatment for 24 mos.
292 patients with 613 matched stenoses at baseline and study end.292 patients with 613 matched stenoses at baseline and study end.
Presented at ACC 08Presented at ACC 08
24 month treatment24 month treatment
Copyleft Clinical Trial Results. You Must Redistribute Slides
0.0
10.0
20.0
30.0
40.0
50.0
60.0
Baseline Study End
• The mean percent The mean percent diameter stenosis diameter stenosis decreased from decreased from 37.3±8.4% to 37.3±8.4% to 36±10.1% after 24 36±10.1% after 24 months of months of rosuvastatin therapy.rosuvastatin therapy.
• There was a There was a progression of progression of atherosclerosis in 6% atherosclerosis in 6% of patients by of patients by >>0.2mm. 0.2mm. M
ean
dia
met
er s
ten
osis
(%
)M
ean
dia
met
er s
ten
osis
(%
)ASTEROID Trial: Mean Diameter StenosisASTEROID Trial: Mean Diameter Stenosis
n = 292n = 292 n =292n =292
p < 0.001p < 0.001
Presented at ACC 08Presented at ACC 08Copyleft Clinical Trial Results. You Must Redistribute Slides
37.3 ± 8.4%37.3 ± 8.4% 36.0 ± 10.1%36.0 ± 10.1%
ASTEROID Trial: LDL-C and HDL-C levelsASTEROID Trial: LDL-C and HDL-C levels
Presented at ACC 08Presented at ACC 08Copyleft Clinical Trial Results. You Must Redistribute Slides
• LDL-C levels were reduced to a mean of 61.1±20.3 LDL-C levels were reduced to a mean of 61.1±20.3 mg/dL (53.3% reduction) after rosuvastatin therapy.mg/dL (53.3% reduction) after rosuvastatin therapy.
HDL-C levels increased from 42.8 mg/dL to HDL-C levels increased from 42.8 mg/dL to 48.3±12.4 mg/dL (13.8% increase) after rosuvastatin 48.3±12.4 mg/dL (13.8% increase) after rosuvastatin therapy.therapy.
CONCLUSION: Treatment of rosuvastatin for 24 CONCLUSION: Treatment of rosuvastatin for 24 months was associated with atherosclerosis months was associated with atherosclerosis regression evidenced by an increase in the minimum regression evidenced by an increase in the minimum lumen diameter and a decrease in percent diameter lumen diameter and a decrease in percent diameter stenosis in patients with coronary artery disease. stenosis in patients with coronary artery disease.
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 smoking
Hypertension (BP ≥140/90 mm Hg or antihypertensive medication)
HDL-C <40 mg/dL
Family history of premature CAD● <55 y in first-degree male relative● <65 y in first-degree female relative
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 disease● Peripheral artery disease● Abdominal aortic aneurysm● Symptomatic carotid artery disease
CAD 10-year risk >20%
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.
No>20%CAD or CAD risk equivalent
Yes0%-10%≥2 RF
No<10%≤1 RF
Need for Framingham Calculation
10-Year Risk for CADRisk Profile
Yes10%-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
1≥280 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 2
≥160 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% ≥17≥30%
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
2≥280 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 5
≥160 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
≤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
≤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 ≥200)
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
I have some bad news for you. While your cholesterol has remained the same, the research
findings have changed.
Lipid Management GoalLipid Management Goal
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*
>100 mg/dL (<100 mg/dL: consider
drug options)
≥100 mg/dL
<100 mg/dL
if TG > 200 mg/dL,
non-HDL-C should be < 130 mg/dL
High risk: CHD or CHD risk equivalents (10-year risk >20%)
and
All patients
Initiate TLC
>100 mg/dL (<100 mg/dL: consider
drug options)
Consider Drug Therapy
<70 mg/dL,
non-HDL-C < 100 mg/dL
LDL-C and non-HDL-C Goal
Risk Category
Very high risk:
ACS or established CHD
plus: multiple major risk factors (especially diabetes) or severe and poorly controlled risk factors
Grundy, S. et al. Circulation 2004;110:227-39.
Lipid Management Goals: NCEPLipid Management Goals: NCEP
ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes
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
Lipid Management Lipid Management RecommendationsRecommendations
If baseline LDL-C > 100 mg/dL, initiate LDL-lowering drug therapy
If on-treatment LDL-C > 100 mg/dL, intensify LDL-lowering drug therapy (may require LDL lowering drug combination)
If baseline is LDL-C 70 to 100 mg/dL, it is reasonable to treat to LDL < 70 mg/dL
Assess fasting lipid profile in all patients, and within 24 hours of hospitalization for those with an acute event. For patients hospitalized, initiate lipid-lowering medication as recommended below prior to discharge according to the following schedule:
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
When LDL lowering medications are used, obtain at least a 30-40% reduction in LDL-C levels.
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Lipid Management Lipid Management RecommendationsRecommendations
If TG are 200-499 mg/dL, non-HDL-C should be < 130 mg/dL
Further reduction of non-HDL to < 100 mg/dL is reasonable
Therapeutic options to reduce non-HDL-C: More intense LDL-C lowering therapy I (B) orNiacin (after LDL-C lowering therapy) IIa (B) orFibrate (after LDL-C lowering therapy) IIa (B)
If TG are > 500 mg/dL, therapeutic options to prevent pancreatitis are fibrate or niacin before LDL lowering therapy; and treat LDL-C to goal after TG-lowering therapy. Achieve non-HDL-C < 130 mg/dL, if possible
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
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
Effect of Mediterranean-style diet in the Effect of Mediterranean-style diet in the metabolic syndromemetabolic syndrome
180 pts with metabolic syndrome randomized to 180 pts with metabolic syndrome randomized to Mediterranean-style vs. prudent diet for 2 yearsMediterranean-style vs. prudent diet for 2 years
Those in intervention group lost more weight (-4kg) than Those in intervention group lost more weight (-4kg) than those in the control group (+0.6kg) (p<0.01), and those in the control group (+0.6kg) (p<0.01), and significant reductions in CRP and Il-6.significant reductions in CRP and Il-6.
After 2 years, 40 pts in intervention group still had After 2 years, 40 pts in intervention group still had features of metabolic syndrome compared to 78 pts in features of metabolic syndrome compared to 78 pts in the control groupthe control group
Esposito K et al. JAMA 2004; 292(12): 1440-6.
Dietary Approaches to Stop Dietary Approaches to Stop Hypertension (DASH)Hypertension (DASH)
Diet high in fruits and Diet high in fruits and vegetables and low-fat dairy vegetables and low-fat dairy products lowers blood products lowers blood pressure more than a pressure more than a sodium-restricted dietsodium-restricted diet
7-8 servings/day of grain/grain 7-8 servings/day of grain/grain products, 4-5 vegetable, 4-5 products, 4-5 vegetable, 4-5 fruit, 2-3 low- or non-fat dairy fruit, 2-3 low- or non-fat dairy products, 2 or less meat, products, 2 or less meat, poultry, and fish.poultry, and fish.
NEJM 1997; 366: 1117-24.NEJM 1997; 366: 1117-24.
Shai I et al. N Engl J Med 2008; 359:229-241.
Weight lossWeight loss
Group Low-fat (kg)
Mediterranean (kg)
Low-carb (kg)
All patients -2.9 -4.4 -4.7All completers -3.3 -4.6 -5.5Men -3.4 -4.0 -4.9Women -0.1 -6.2 -2.4
Weight Loss with a Low-Carbohydrate, Mediterranean or Low-Fat Diet: Dietary Intervention Randomized Controlled Trial (DIRECT)
322 moderately obese subjects, mean age 52, mean BMI 31, 86% male, randomized to one of three diets for 2 years. Adherence 95% at 1 year, 85% at 2 years.
Shai I et al. N Engl J Med 2008; 359:229-241.
Lipid changesLipid changes
Parameter Low-fat (mg/dL)
Low-carb (mg/dL)
Mediterranean (mg/dL)
HDL +6.4 +8.4 +6.3LDL -0.05 -3.0 -5.6Triglycerides -2.8 -23.7 -21.8TC/HDL ratio -0.6 -1.1 -0.9
Conclusions: Mediterranean and low-carbohydrate diets may be effective alternatives to low-fat diets. Favorable effects on lipids from the low carbohydrate diet and on glycemic control from the Mediterranean diet suggest diets may be tailored to individual needs/preferences.
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.
–36 mg/dlTotal
–16Plant stanols/sterols (2 g/d)
–8Viscous fiber (10–25 g/d)
–12Low saturated fat/dietary cholesterol
LDL-C ↓ (mg/dL)Dietary Component
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.
Good↓ 9%↑ 1%↓ 18%↓ 13%Ezetimibe
Good↓ 14-29%↑ 4-12%↓ 25-50%↓ 19-37%Statins*
Good↓ 30%↑ 11-13%↓ 4-21%↓ 19%Fibrates (gemfibrozil)
Poor to reasonable
↓ 30-70%↑ 14-35%↓ 10-20%↓ 10-20%Nicotinic acid
PoorNeutral or ↑↑ 3%↓ 10-18%↓ 7-10%Bile acid sequestrants
Patient tolerability
TGHDLLDLTCTherapy
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.
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.
Drug TherapyDrug Therapy
HMG CoA Reductase Inhibitors (Statins)HMG CoA Reductase Inhibitors (Statins)
Reduce LDL-C 18–55% & TG 7–30%Reduce LDL-C 18–55% & TG 7–30%
Raise HDL-C 5–15%Raise HDL-C 5–15%
Major side effectsMajor side effects
− MyopathyMyopathy
− Increased liver enzymesIncreased liver enzymes
ContraindicationsContraindications
− Absolute: liver diseaseAbsolute: liver disease
− Relative: use with certain drugsRelative: use with certain drugs
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
Atorvastatin
Pravastatin
Rosuvastatin
Simvastatin
10 mg 20 mg 40 mg 80 mg
Dose
*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 mg• Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160. • Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.
*
**†
–60
–50
–40
–30
–20
–10
0
Mea
n P
erce
nt
Chan
ge
From
Bas
elin
e 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
When LDL-lowering drug When LDL-lowering drug
therapy is employed in high-risk therapy is employed in high-risk
or moderately high risk patients, or 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.
Grundy et al. Circulation. 2004;110:227-239.
Doses of Statins Required to Attain 30-40% Reduction of LDL-C
3910Atorvastatin
39-455-10Rosuvastatin
25-3540-80Fluvastatin
35-4120-40Simvastatin
3440Pravastatin
3140Lovastatin
LDL Reduction, %
Dose, mg/d
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:
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 effects● GI distress/constipation● Decreased absorption of other drugs (1st generation)
Contraindications● Dysbetalipoproteinemia● 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 ββ-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
ha
ng
e f
rom
bas
elin
ea
t w
k 2
4
TGHDL-CLDL-C
*
†
Placebo (n=88)
Colesevelam 3.8 g/d (n=95)
Colesevelam Monotherapy: EfficacyColesevelam Monotherapy: Efficacy
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%