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Dyslipidemia and Dyslipidemia and AtherosclerosisAtherosclerosis
Eliot A. Brinton, M.D.Eliot A. Brinton, M.D.Associate ProfessorAssociate Professor
Cardiovascular GeneticsCardiovascular GeneticsDivision of CardiologyDivision of Cardiology
Department of Internal MedicineDepartment of Internal MedicineUniversity of Utah School of MedicineUniversity of Utah School of Medicine
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0
200
400
600
800
1000
1200
1400
0.9 0.95 1 1.05 1.1 1.15 1.2 1.25
Density
Dia
met
er (a
ngst
rom
s)
HDL2HDL2 HDL3HDL3
LDLLDLIDLIDL
VLDLVLDL
ChylomicronChylomicron
1.0061.006
plasmaplasmapre-pre-ββ HDL HDL
Lipoproteins by Size and DensityLipoproteins by Size and Density
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Pre-β HDL
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AdiposeAdipose
HeartHeart
MuscleMuscle
Lipoprotein LipaseLipoprotein Lipase
HMG CoA ReductaseHMG CoA Reductase
Dietary CholesterolDietary Cholesterol100-500 mg/day100-500 mg/day
(40-50% absorbed)(40-50% absorbed)
Bile acids 300 mgBile acids 300 mgCholesterol 600 mgCholesterol 600 mg
Biliary Biliary Chol.Chol.
700 mg/day700 mg/day
Bile Bile Acids Acids
20 g/day 20 g/day 98.5% 98.5%
reabsorbedreabsorbed
TRIGTRIGketone bodiesketone bodies
COCO22, H, H22OO
OtherOtherTissuesTissues
intestine, skin, intestine, skin, adrenal, ovary, adrenal, ovary,
testes, testes, atheroma / atheroma /
macrophagesmacrophages
VLDLVLDL
Apo C’sApo B-100
Apo E
IDLIDL
Hepatic LipaseHepatic Lipaseapo Eapo E
LDLLDL
pre-pre-ββ11 HDL HDL
(two apo A-I)(two apo A-I)
pre-pre-ββ22 HDL HDL
(+PL=disc)(+PL=disc)
pre-pre-ββ33 HDL HDL
(+UC in disc)(+UC in disc)
HDLHDL33
PLPLFCFC
LCATLCAT
PLPLFCFC
““LDL Pathway”LDL Pathway”
LDL ReceptorsLDL Receptors
CETPCETPTGTG
CECE
HDLHDL2a2a
HDLHDL2b2b
Hepatic Hepatic LipaseLipase
CHOLCHOL
Dietary Fat Dietary Fat 60-100 g/day (98% absorbed)60-100 g/day (98% absorbed)
free fatty free fatty acidsacids
ChylomicronChylomicron
Apo B-48(Apo A-I)
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Familial Familial Hypercholesterolemia Hypercholesterolemia
(FH)(FH)
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LDLLDL
AdiposeAdipose
HeartHeart
MuscleMuscle
Lipoprotein LipaseLipoprotein Lipase
Bile Bile Acids Acids
CHOLCHOL
ffaffa VLDLVLDL
TRIGTRIG
““LDL Pathway”LDL Pathway”
HMG CoA ReductaseHMG CoA Reductase
OtherOtherTissuesTissues
ketone bodiesketone bodies
COCO22, H, H22OO
IDLIDL
HDLHDL
FamilialFamilialHypercholesterolemiaHypercholesterolemia
(heterozygous)(heterozygous)
½ normal ½ normal LDL ReceptorsLDL Receptors
StatinsStatins
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Non-Fatal CAD in FH (Utah) Non-Fatal CAD in FH (Utah) vs. General U.S. Populationvs. General U.S. Population
0
0.01
0.02
0.03
0.04
0.05
Age
Non-FH Women
FH Women
0
0.05
0.1
0.15
0.2
0.25
0.3
Age
Cu
mu
lati
ve P
rob
abil
ity
of
Cli
nic
al C
AD
Non-FH Men
FH Men
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What FH May Mean for a What FH May Mean for a FamilyFamily
45 45 ♥♥334334
47 47 ♥♥
4242218218
38 38 ♥♥ 34 34 ♥♥347347
40 40 ♥♥373373
41 41 ♥♥ 34 34 ♥♥
1616284284
18189494
2020182182
4242180180
3131158158
1212132132
1717157157
1818285285
1919130130
2121311311
2222135135
66291291
1313344344
1414118118
1515255255
40 40 ♥♥373373
AffectedAffectedAge at MIAge at MITotal CholTotal Chol
KeyKey
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““Pure” HypercholesterolemiaPure” HypercholesterolemiaMonogenic SyndromesMonogenic Syndromes
Familial hypercholesterolemia (FH)Familial hypercholesterolemia (FH)• LDL receptor mutations (over 800 distinct types)LDL receptor mutations (over 800 distinct types)• 1/500 in general population (heterozygotes)1/500 in general population (heterozygotes)
Familial defective apo B (FDB) (Familial defective apo B (FDB) (minorityminority of FH) of FH)• Ligand defect Ligand defect notnot receptor defect receptor defect• Apo B mutations (3500, etc.)Apo B mutations (3500, etc.)
PCSK9PCSK9 mutations (rel mutations (rel rarerare, 1/50 FH families), 1/50 FH families)
Autosomal recessive hypercholest. (Autosomal recessive hypercholest. (v. rarev. rare))
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““Pure” HypercholesterolemiaPure” HypercholesterolemiaOther causesOther causes
Polygenic hypercholesterolemiaPolygenic hypercholesterolemia• Very Very CommonCommon• Genetics poorly definedGenetics poorly defined• Mechanisms poorly defined (likely includes Mechanisms poorly defined (likely includes
hyperabsorbers)hyperabsorbers)• Generally Generally milder milder than FHthan FH
Diet-inducedDiet-induced• Very Very commoncommon• Generally Generally much milder much milder than FHthan FH
““Secondary” causesSecondary” causes• Hypothyroidism—rel. Hypothyroidism—rel. common in elderly common in elderly but but ↑↑LDL LDL mildmild• Other (Other (rare rare hepatic and renal abn., etc.)hepatic and renal abn., etc.)
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VLDL overproductionVLDL overproduction
Associated Lipid Abnormalities:Associated Lipid Abnormalities:• Mild-moderate Mild-moderate ↑↑VLDL-C/Plasma TGVLDL-C/Plasma TG• Mild-moderate Mild-moderate ↓↓HDL-C HDL-C • Small, dense LDL (and HDL)Small, dense LDL (and HDL)• Mild Mild ↑↑LDL-CLDL-C
11oo mechanism of familial combined mechanism of familial combined hyperlipidemia (FCHL) and familial HTG hyperlipidemia (FCHL) and familial HTG (mechanism of (mechanism of difference undifference unclear)clear)
Strongly associated with central adiposity:Strongly associated with central adiposity:• Major mechanism for Major mechanism for ↑TC ↑TC and and ↑↑TG with aging TG with aging • Almost always helped by weight lossAlmost always helped by weight loss
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Metabolic Syndrome
DM-2
FCHL
↑Apo B???
?
“Classic” DM-2
“Isolated” ↑Apo B
“Isolated” Metabolic Syndrome
Adapted from John Brunzell, personal communication, 2005Adapted from John Brunzell, personal communication, 2005
Overlap Among Metabolic Syndrome, Diabetes Mellitus-2, ↑Apo B and FCHL
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Despite Elegant Science of Despite Elegant Science of Abnormalities Abnormalities
of Lipoprotein Metabolism,of Lipoprotein Metabolism,Treatment of Dyslipidemias Treatment of Dyslipidemias
is Nearly is Nearly AlwaysAlways Just Just According to Lipid Levels!According to Lipid Levels!
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Atheroprevention in Diabetes
Mellitus
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National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
Atherosclerosis in Diabetes
• ~80% of all diabetic mortality– 75% from coronary atherosclerosis– 25% from cerebral or peripheral vascular
disease
• >75% of all hospitalizations for diabetic complications
• >50% of patients with newly diagnosed type 2 diabetes already have CHD
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Cholesterol Predicts CHD Mortality Rate in Diabetic and Nondiabetic MenMultiple Risk Factor Intervention Trial (MRFIT)
Cholesterol Predicts CHD Mortality Rate in Diabetic and Nondiabetic MenMultiple Risk Factor Intervention Trial (MRFIT)
0
20
40
60
80 Diabetic Nondiabetic
Rat
e/10
00
1 2 3 4 5
Serum Cholesterol Quintile Bierman EL, Arteriosder Thromb, June 1992Based on data from J. Stamler
●
● ●
●
●
●●●●●
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0
10
20
30
40
50
Diabetes and glucose intolerance vs. cardiovascular mortality
MenWomen
Bedford Study, Keen, et al. Lancet. 2:505–508, 1965.
10 y
ear
CV
D m
orta
lity
(%)
Normal IGT DM Normal IGT DM
40-59 60+
Age (years)
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HBP Inflam, cytokines insulin Gluc/DM
(ox/glycox) TG Dense
LDLLow HDL Coag.
Endothelial dysfunction
Insulin Resistance
Interrelationship Between Obesity, Insulin Resistance, DM and Atherosclerosis
Obesity, etc.
Atherosclerosis
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ATP III: Insulin Resistance Syndrome (“The Metabolic” Syndrome* ICD9 277.7)
*3 risk factors = Insulin Resistance†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.
<40 mg/dL<50 mg/dL
MenWomen
>102 cm (>40 in)>88 cm (>35 in)
MenWomen
100 mg/dLFasting glucose
130/85 mm HgBlood pressure
HDL-C
150 mg/dLTG
Abdominal obesity† (Waist circumference‡)
Defining LevelRisk Factor
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Insulin Resistance Syndrome Prevalence:NHANES III Data; ATP III Criteria
• 24% of total US Population (47 million pts)• 32% of US Hispanics• 26% higher Hispanic women vs. men• 57% higher in Black women vs. men• 43% of total population > 60 y old
Ford E, et al JAMA 287:356-9, 2002
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Fredrickson Type III Fredrickson Type III (Familial Dysbetalipoproteinemia)(Familial Dysbetalipoproteinemia)
DefinitionDefinition
TGRL remnant (IDL) excessTGRL remnant (IDL) excess
VLDL-C/Plasma TG VLDL-C/Plasma TG 0.30, TG >150 mg/dl 0.30, TG >150 mg/dl
Apo E 2/2 + other abn (VLDL overprod?); Apo E 2/2 + other abn (VLDL overprod?); or or apo E deficiencyapo E deficiency
Palmar (flat and orange) and/or tuberoeruptive (elbow) Palmar (flat and orange) and/or tuberoeruptive (elbow) xanthomasxanthomas
Prevalence and Athero RiskPrevalence and Athero Risk
193 NIH referrals for TG >190 mg/dl and familial 193 NIH referrals for TG >190 mg/dl and familial lipids, 49 ( lipids, 49 (25%!25%!) ) had type III. had type III.
37% of these type III patients had CAD (average onset of 38 yo)37% of these type III patients had CAD (average onset of 38 yo)
Fredrickson DS, Morganroth J, Levy RI. Ann Intern Med 1975; 82:150-157Morganroth J, Levy RI, Fredrickson DS. Ann Intern Med 1975; 82:158-174
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TG and HDL vs. Risk of Premature CAD653 cases, 1029 controls. Multiple logistic model included age, gender, BMI, DM,
cigarette smoking and LDL cholesterol
1.0
2.8
2.2
4.0
8.3
0 2 4 6 8 10
TG <200, HDL 40+
TG 200-799, HDL 40+ (p <0.000)
TG <200, HDL <40 (p <0.0001)
TG 200-799, HDL <40 (p <0.0001)
Definite Type III (p <0.0001)
Odds Ratio
Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.
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LDL-C at follow-up (mg/dL)
0
5
10
15
20
25
30
90 110 130 150 170 190 210
Perc
en
t w
ith
C
HD
even
t
CARE--Rx
LIPID-Rx
4S-Rx
CARE-PILIPID-PI
4S-PI
2° Prevention
1° PreventionWOSCOPS-PI
WOSCOPS-Rx
AFCAPS/TexCAPS-Rx
AFCAPS/TexCAPS-PI
GREACE-UC
GREACE-Rx
HPS 2o-Pl
CPPT-PlCPPT--Rx
POSCH-Pl
POSCH—Rx
HPS 2o-Rx
HPS 1o-Pl
HPS 1o-Rx
CHD Events vs. LDL-C: Statin and Non-Statin Trials
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NCEP ATP Update—2004 Risk Category Risk Factors LDL-C Goal Lower 0-1 RF <160Mod/Mod-High >2 RF, FRS <20% <130 High CVD alone or FRS >20% <100Very High CVD+DM, MS, ↑↑RF, ACS <70*
•In High and Very High Risk categories–Consider statin Rx even if already at goal–Consider combination Rx—statin + fibrate or niacin—if TG>200+NHDL-C>130 or HDL-C<40
•Statin Rx for 30-40% ↓LDL-C (R-5, A-10, S-20, F,L,P-40) in > mod. high risk vs. don’t use lower doses•65-80 yrs: 2o prev as younger; 1o prev+DM=high risk; other, use clinical judgment•Non-HDL-C: use if TG>200; goal as LDL-C+30
Grundy, et al. Implications of Recent Clinical Trials for NCEP ATP III. Circ. July 13, 2004;110:227-239.
*Therapeutic option: use clinical judgment
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More Aggressive Lipid Treatment“BEIGE”
• Broader use of treatment (TLC and meds)
• Earlier use of medications (may not wait for TLC)
• Increased intensity of Rx
• Getting to goal
• Evaluation of progress, follow-up (esp. compliance which is <50% at 1 year!!!)
Modified from AM Gotto AHA mtg 11/05
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Factors Not Included in the Framingham Risk Score
• CVD (FRS designed for 1o prevention)
• Diabetes Mellitus (FRS not used in DM in ATP III)
• Metabolic Syndrome (TG, glucose, obesity, DBP)
• Family History of CHD
• Emerging risk factors
• Diet and exercise
• Higher risk in non-Caucasians
• Further risk increase above 79 years old
• Risk beyond 10 years in future (underestimates risk in young adults)
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May adjust the LDL-C goal from NCEP table
up or down by 30 mg/dl per:
1. Position within risk category (add if risk, subtract if ), or factors not in Framingham score (e.g. DM, IR)
2. Overall health (add if quality/ quantity, subtract if )
3. Patient’s wishes (add if fears Rx, subtract if fears
atherosclerosis)
Clinical Judgment for NCEP ATP Update—2004
(per Dr. E. A. Brinton)
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Choice of HMG-CoA Reductase Inhibitors
(“Statins”)1. Lovastatin (Mevacor, Altoprev, generic)—events (1o prev.),
longer experience, generic and extended release available
2. Pravastatin (Pravachol)—v. good event data (1o and 2o prevention), safer in combo?
3. Simvastatin (Zocor)—best 2o prev. data, DM/2o prev. indication (any LDL-C), max efficacy, cost effective ( events)
4. Fluvastatin (Lescol)—athero and events, cost effective (low-mod lowering), safer in combo?
5. Atorvastatin (Lipitor)—good event data (A80 > P40 or A10, 2o prev), max effic., cost eff. (mid LDL-C), good CRP
6. Rosuvastatin (Crestor)—max efficacy, v. cost-effective ($17/mo for ½ of R40 qod), event data pending, safety = other statins, good CRP, better resp. to added ezet?
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Diet (Medical Nutrition Therapy, MNT), and
Lifestyle (Therapeutic Lifestyle Change, TLC) for
Atheroprevention
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Intensive Lifestyle Changes and Intensive Lifestyle Changes and CAD ReversalCAD Reversal (Ornish D, et al. JAMA 1998; (Ornish D, et al. JAMA 1998;
280:2001)280:2001)
42.3
51.9
37.340.7
38.5
41.3
30
35
40
45
50
55
Baseline 1 year 5 years
Dia
met
er S
teno
sis
(%)
Control
Treament
-6.81
-3.01
-0.37
-8
-7
-6
-5
-4
-3
-2
-1
0
MostAdherent
(n=6)
MediumAdherent
(n=7)
LeastAdherent
(n=6)
Ch
ang
es i
n D
iam
eter
Ste
no
sis
(% i
n 5
y)
p = 0.02 p = 0.001p = 0.02 p = 0.001
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180
200
220
240
260
280
300
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
Year
Ser
um C
hole
ster
ol (m
g/dl
)
Hospital K
Hospital N
Finnish Mental Hospital StudyFinnish Mental Hospital Study
Study Design and Serum Study Design and Serum CholesterolCholesterol
Diet changed in Diet changed in hospital Nhospital N
Diets reversedDiets reversed
Data for males Data for males shown here. shown here. Total in each Total in each hospital about hospital about 3500. About 70-3500. About 70-75% remained 75% remained in hospital all 12 in hospital all 12 yearsyears
Miettinen M, et al. Lancet 1972; ii: 835Miettinen M, et al. Lancet 1972; ii: 835
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Finnish Mental Hospital StudyFinnish Mental Hospital Study
Age-adjusted death-rates Age-adjusted death-rates (per 1000 (per 1000
person-years)person-years)
MalesMales FemalesFemales
CHDCHD TotalTotal CHDCHD TotalTotal
Hospital N, dietHospital N, diet 5.75.7 34.634.6 4.04.0 31.131.1
Hospital N, controlHospital N, control 13.013.0 38.838.8 7.77.7 32.132.1
Hospital K, controlHospital K, control 15.215.2 40.240.2 8.18.1 25.925.9
Hospital K, dietHospital K, diet 7.57.5 35.135.1 6.56.5 30.730.7
Pooled dietPooled diet 6.66.6 34.834.8 5.25.2 30.930.9
Pooled controlPooled control 14.114.1 39.539.5 7.97.9 29.029.0
Miettinen M, et al. Lancet 1972; ii: 835Miettinen M, et al. Lancet 1972; ii: 835
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Non-Medical Treatments (TLC)for Dyslipidemias
Diet (MNT)• Low saturated fat (5-10% ↓LDL-C); low cholesterol?• Whole grains, fruits, vegetables, legumes, non-fat
dairy? hard water? (~5% ↓LDL-C)
• Supplements– Plant sterol/stanol ester margarine (5-10% ↓LDL-C)– Soluble fibers (~5% ↓LDL-C)– Red Yeast Rice/Cholestin (lovastatin + other statins?)—% ↓LDL-C & safety issues not
well documented– Niacin (Rx effective but AHA recommends against DS NA for lipids)– Fish oil (Rx effective but AHA and FDA against DS ω-3 at TG ↓doses, DS ok anti-plt)– Flaxseed oil (little conversion to EPA/DHA, few data, ok for vegans)– Phospholipids, garlic, biotin, etc. not well documented– Folate, B6, B12—↓Hcy but ↓CVD not seen yet
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Non-Medical Treatments for Dyslipidemias (cont.)
Exercise• How? (aerobic, anaerobic, stretching all beneficial)• How often? (2/wk to constant)• What benefits?
– ↓Obesity, ↑mood/↓depression, ↓insomnia,– Plasma factors: ↓TG, ↑HDL-C, ↑ LDL size?, ↓Glucose, ↓CRP?– ↑Collateral vessels– ↓CVD (but protection not absolute)– ↑Longevity
Smoking Cessation• Will to quit essential• Non-medical treatment effective (hypnosis, behavior modif.)• Several good medications available
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Atheroprevention Beyond LDL-C and
Statin Monotherapy: Non-Statin Treatment
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CHD Risk Prediction byHDL-C vs. LDL-C*
0.0
1.0
2.0
3.0
100 160 220 8565
4525
LDL-C (mg/dL)
HDL-C (mg/dL)
Adapted from and reprinted with permission from Castelli WP. Can J Cardiol. 1988;4(suppl A):5A.
RR of CHDAfter 4 yr
*Data represent men age 50–70 yr from the Framingham Study.
Patient 2:LDL-C: 100 mg/dLHDL-C: 25 mg/dL
Patient 1:LDL-C: 220 mg/dLHDL-C: 45 mg/dL
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Univariate Regression
R2
N=44,170; total CHD events = 3869R2 denotes the proportion of variance. TC = total cholesterol.
Rx Changes HDL and TC/HDL are Best predictors of CHD Risk Reduction
0.45
0.53 0.55
0.65 0.65
0.86
0
0.2
0.4
0.6
0.8
1
TG LDL TC Non-HDL HDL TC/HDL
Alsheikh-Ali AA, et al. Increases in HDL-C are the strongest predictors of risk reduction in lipid intervention trials [poster]. AHA Scientific Sessions 2004; November; New Orleans, La.
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Hypothesized Antiatherogenic Mechanisms of HDL
• Reverse cholesterol transport
• Antioxidant effects
• Anti-inflammatory effects
• Anti-thrombotic effects?
• Direct blocking of LDL effects?
• Other?
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Reverse Cholesterol Transport
A-I
Liver CECE
UCPL&UCLCAT
UC
Bile
SR-BI
A-I
ABCA1
Macrophage
CE B
CETP = cholesteryl ester transfer proteinLDL = low-density lipoprotein LDLR = low-density lipoprotein receptorVLDL = very-low-density lipoprotein
Adapted from C Cuchel et al. Art Thromb & Vasc Biol 2003;23:1710-12
LDL-R
VLDL/LDL
CETP
Mature HDLNascent HDL
CE
SR-A
Oxidation
PL
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12-Lipoxygenase12-Lipoxygenase
HPODEHPODEHPETEHPETE
Oxidized Oxidized LDLLDL
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Medications which Raise HDL-C Levels
Agent HDL-C Effect
Nicotinic acid 15-35%
Fibrates 5-20%
Statins 5-15%
TZD’s (esp pio) 5-20%
Estrogens 10-25%
-blockers 10-20%
Alcohol 5-10%
Belalcazar LM et al. Progress in Cardiovascular Disease 1998;41:151-174.
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Effect of Niaspan on Lipids and Glycemic Control in Effect of Niaspan on Lipids and Glycemic Control in Patients with Diabetes Mellitus (ADVENT)Patients with Diabetes Mellitus (ADVENT)
Fasting Blood Glucose*
0
50
100
150
200
250
Placebo Niaspan 1 gram Niaspan 1.5 grams
Glu
co
se
mg
/dL
Baseline Week 4 Week 8 Week 12 Week 16
Grundy et al, Arch Int Med 162:1568-76, 2002* median values
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0
5
10
15
20
<95 95-104 105-125
CDP at 6 yr: Nonfatal MI by Baseline FBG*
mg/dL
RelativeHazard 0.70 0.74 0.73 0.44
*Z for interaction = –0.35. Indicates homogeneity
Eve
nt
Rat
e (%
)
126
Placebo Niacin
Canner PL et al. Am J Cardiol. 2005 Jan 15;95(2):254-7.
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Niacin Reduces MI Regardless of Increase in Fasting Glucose
Change in FPG (baseline to 1yr)CDP data. Canner PL et al. Am J Cardiol. 2005 Jan 15;95(2):254-7.
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Maximizing Niacin Tolerability
• Niacin ER (Niaspan), or ERNL (Advicor), far less flushing than IR (?SR qd?)
• Take with – ASA 325mg (buffered, not enteric-coated) vs. Alka-Seltzer– Diphenhydramine (Benadryl) 25-50 mg– CaCO3 (Tum) vs. snack (vs. buffered ASA)
• Gradual uptitration (1 mo each at 500 and 1000 mg/d, re-do if off > 2 wks)
• Avoid with: EtOH, hot liquids, spicy foods• Consider dosing in am (vs. hs)• Watch glucose (also uric acid/gout, GI Sx if Hx)• Remind pt: flushing not harmful, niacin is a vitamin, D/C
antioxidants!
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No-Flush Niacins
Types• Niacinamide/Nicotinamide• Acipimox• Inositol HexaniacinateLipid Effects• Few or noneEvidence for CHD Prevention• None
Not recommended for atheroprevention!
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HDL- Clinical SummaryLevels--Basal vs. Intervention1. HDL is protective, but
2. Lowering it may not be bad (e.g. good diet), and
3. Raising it may not be good (data not definitive)
4. LDL/HDL ratio estimates risk but confuses Rx
Treatment (goal >40 mg/dl in men >50 in women)1. Not Diet (bad diet is bad, high mono unproven)
2. Not Ethanol (adverse events, bene. unproven)
3. Lifestyle: wt loss, exercise, smoking cessation
4. Meds: niacin (↑effective but ↑Sx), fibrates, statins or TZD’s (less effective but fewer Sx)
Use med Rx to ↑HDL only in 2o and high-risk 1o prev
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TG and HDL vs. Risk of Premature CAD653 cases, 1029 controls. Multiple logistic model included age, gender, BMI, DM,
cigarette smoking and LDL cholesterol
1.0
2.8
2.2
4.0
8.3
0 2 4 6 8 10
TG <200, HDL 40+
TG 200-799, HDL 40+ (p <0.000)
TG <200, HDL <40 (p <0.0001)
TG 200-799, HDL <40 (p <0.0001)
Definite Type III (p <0.0001)
Odds Ratio
Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.Hopkins PN, Wu LL, Hunt SC, Brinton EA. JACC 2005 Apr 5;45(7):1003-12.
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0
10
20
30
40
50
60
70
80
90
100
20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 500
Phenotype APhenotype B
% Cumulativefrequency
TG (mg/dL)Austin M et al. Circulation. 1990;82:495-506.
LDL Phenotypes/Patterns A and B (B=SD LDL) vs. Plasma TG
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Extra Atherogenicity of Small Dense LDL (pattern B)
EndothelialChemoattractants
FOAM CELL
Highly oxidizedSmooth
Muscle Cell
Mildly oxidized
Macrophage
LDL
LDLENDOTHELIUM Monocyte
Macrophage
Through endothelium easier
Stays on matrix longer
More readily oxidized
Associates w/ Metabolic Syndrome/DM:↓HDL, ↑TG, ↑Inflam., ↑Thromb., ↑Oxid.
↓LDL-R uptake, ↑ Levels & Modific.
And
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LDL-C Doubly Underestimates CHD Risk with Small-Dense LDL
• More particles/LDL-C →higher LDL particle # than suspected
– e.g. LDL-C 100 → ↑risk ≈ 120 mg/dl
• More atherogenic/LDL particle than large LDL
– e.g. LDL-C 120 ↑risk ≈ 140 mg/dl
LDL-C looks low but CHD risk is high
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Test (method)
• Berkley Heart Lab (GGE), Lipo Print
• LipoProfile/ LipoScience (NMR)
• VAP/Atherotech (Ultracentrifugation)
Pro/Con• Established method, well
validated, rel. pricey ($99-$240 and up, a la carte)
• More affordable (~$120), new method but well validated, LDL particle #, no extras
• Established method, well validated, CDC std, very affordable ($45-$90), MetSynd, Lp(a)-chol gratis
Advanced Lipid Profiles—Which?
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Rx of Small, Dense LDL
Increase LDL Size• Niacin• Fibrates• TZDsLower LDL-C• Statins• Niacin, CAI, BAS, fenofibrateRx Insulin Resistance• Diet, exercise, weight loss• TZD’s• Metformin? ACEI’s?
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Non-Pharmacological Approaches to Hypertriglyceridemia
• Consider secondary causes (increased frequency)
– Poorly controlled diabetes mellitus
– Hypothyroidism
– Corticosteroids / Cushing’s
– Isotretinoin (Accutane) (rarely a problem)
• Weight loss, exercise
• Avoid sugar and high carbohydrate diet
• Fish and fish oil
• Little or NO ALCOHOL
• Change oral estrogen to patch or discontinue
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Lipid Effects: Fenofibrate vs SimvastatinM
ean
(%)
chan
ge f
rom
bas
elin
e
Steinmetz A et al., J Cardiovasc Pharmacol 1996 Apr;27 Suppl:S63-70
Double-blind, randomized, controlled 12 week trial
Type IIa and IIb Patients
-50
-40
-30
-20
-10
0
10
20
Total Chol LDL TG HDL fibrinogen uric acid
fenofibrate 200mg mic. (n=66) simvastatin 20mg (n=64)
-20-25
-21
-35
-41
-17
+18+15
-10
+4
-25
0
P=0.05 P=0.001 P=0.001 P=0.015 P=0.001 P=0.001
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Gemfibrozil (Lopid and generic) vs.
Fenofibrate (TriCor, Antara, Tryglide, generic)
Favor Gemfibrozil
• Cost (generic)
• Availability (generic)
• Better CHD event ↓ data (Helsinki & VA-HIT)
Favor Fenofibrate
• Statin compatibility
• Dosed qd w or w/o meal (ease & compliance)
• Better lipid effects (esp. ↑HDL, ↓LDL)
• ↓Fibrinogen
• ↓Atherosclerosis (DAIS)
• ↓Athero events (FIELD)
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Niacin vs. Fibrates for Mixed Dyslipidemia, DM & Met. Synd.
Favoring Fibrates• Exc ↓TG
• OK ↑HDL
• OK ↓LDL (feno only)
• No flushing
• No increase in glucose levels
• No increase in gout/uric acid
• No increase in Hcy
• ↓CHD event data (gemfib, trend w/ feno)
• Some ↓Lp(a) (feno)
Favoring Niacin• Exc ↑HDL-C
• OK ↓LDL
• OK ↓TG
• Fewer GI Sx (N & V)
• Better Lp(a) lowering
• ↓CHD event data (CDP)
• Better ↓CHD event data in combo w/ statin and/or BAS
• ↓Total mortality
• Better compatibility w/ statin (vs. gemfib.)
• Statin combo tablet (ERNL, Advicor)
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Efficacy Comparison in Patients with TG ≥ 500 mg/dLRelative Difference vs. Placebo
Source: Omacor® Prescribing Information; Antara® 130 mg Prescribing Information.
Omega-3 AEE Fenofibrate
Lipid Efficacy of Omega-3 AEE is Similar to Fenofibrate
-70%
-50%
-30%
-10%
10%
30%
50%TG HDL-C CHOL VLDL-C LDL-C
-70%
-50%
-30%
-10%
10%
30%
50%TG HDL-C CHOL VLDL-C LDL-C
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Dose-Range of Omega-3 FA Effect on Triglycerides
TG 177-442 mg/dL at baseline; 8-week treatmentSource: Data on file at Pronova/Reliant.
---------Dose of O3AEEs ---------
-8.2% -12.0%
-30.0%-43.0%
-60%
-40%
-20%
0%
Placebo 2 g/d 4 g/d 8 g/d
% C
ha
ng
e T
G (
mg
/dL
)
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GISSI-Prevenzione TrialOmega-3 Acid Ethyl Esters
Reduce All-Cause and Sudden Death
Control Omacor® RR P-ValueAll-Cause Mortality 10.6% 8.4% 21% 0.0064Sudden Death 3.3% 1.8% 44% 0.0006
Days
1.00
0.99
0.98
0.97
0.96
0.95
Pro
bab
ilit
y
330210150600 90 180 27030 120 240 300 360
0.59 (95% CI 0.36-
0.97) P=0.037
Omega-3 AEE
Control
Marchioli R, et al., Circulation 2002;105:1897-1903.
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Non-Lipid Atherosclerosis and Cardiac Effects of Omega-3 FA
• ↓Malignant ventricular arrhythmias (via cardiac membrane enrichment)
• ↑ICD triggering (malignant ventr. arrhythmias)
• ↓Heart rate and ↑HR variability (via ↑parasympathetic tone, altered cytokine levels?)
• ↑Endothelial relaxation (via ↑NO &↑NO independent mech.)
• ↓Blood Pressure
• Anti-proliferative effect/ ↓smooth-muscle cell proliferation
• Antithrombotic effects (↓platelet reactivity, ↓AA)
• ↓Plasma viscosity
• Anti-inflammatory effects
– ↓Inflammatory cytokines (interleukins, TNF)
– ↓Mitogens
– ↓Cell-adhesion molecule expression
– Altered eicosanoid synthesis (↓AA)
• ↑PON (antioxidant on HDL)
• ↓CHF?
• ↓Sudden Death
• ↓Total and CVD mortality
Holub BJ, CMAJ 2002;166(5):608-15.
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Suggestions for Improving Omega-3 FA Tolerability
•Use O3-AEE’s – fewer capsules, fewer impurities
•Take at start of meal
•Freeze/refrigerate capsules (PI says no)
•Gradual uptitration
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Mortality Effects of Lipid Rx
Rx # Trials
N % Δ Total
% Δ CVD
% Δ non-CVD
Statins 35 53K ↓13%* ↓22%* ↓3%
Omega-3 14 10K ↓23%* ↓32%* ↓3%
Fibrates 17 14K 0% ↓7% ↑13%*
*p<0.01. M Studer, et al. Arch Int Med 2005;165:725-36.
----------Mortality----------
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Fibrates vs. Omega-3 to Rx HTG and Prevent Atherosclerosis
Favoring Fibrates• More conventional• ↓CVD• Better ↑HDL-C & ↓LDL-C • Non-lipid benefits?• Good statin compatibility
(feno only, FIELD)• More convenient (fewer
capsules)• No fishy burping
Favoring Omega-3• More natural• ↓CVD and ↓total mortality• Non-lipid benefits?• No transaminase
contraindic. • No precaution w/ statins• No warfarin interaction• Less nausea and vomiting
Bottom line: •Either is good as first-line •Both often needed in combination!
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Hypertriglyceridemia Drug Treatment
When—After diet and Rx 2o factors• Treat all TG > 500 for pancreatitis & athero• Treat to <150 if 2o prevention, DM/IR or other athero
risk How• Gemfibrozil/Fenofibrate—easier, more effective• Niacin—cheap/easy, best if HDL-C and/or LDL-C • Statins—consider, especially if LDL-C• Omega-3 oils, effective in high doses• TZDs (pioglitazone > rosiglitazone)
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Use Non-HDL-C Instead of LDL-C if TG > 200 (ATP III)
LDL-C Target Non-HDL-C Target
Patient Category (mg/dL) (mg/dL)
No CHD, 0-1 risk factors < 160 <190
No CHD, 2+ risk factors < 130 <160
CHD/CHD risk equivalent < 100 <130
CVD + DM/MS/Cigs/ACS < 70 <100
Non-HDL-C goal = LDL-C goal + 30 Rx to ↓Non-HDL-C:
•If TG <~400 Rx as LDL-C•If TG >~400 Rx as HTG
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Hepatic Source of Inflammatory Markers: CRP, Fibrinogen, SAA
Rader. N Engl J Med 2000;343:1179.
CRPFibrinogen
SAA
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Lp(a)—Summary• Pro-atherogenic/pro-thrombotic factor• Genetically determined • Not lowered by most treatments:
– Diet– Exercise– Weight loss– Statins, – Bile acid resins, – Gemfibrozil
• Rx options:– Lower Lp(a)
Niacin Estrogen Fenofibrate?
– Extra LDL-C lowering
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Suggested Use of Emerging CHD Risk-Factor Tests
Blood Tests• SD LDL• Apo B vs. LDL # vs. Non
HDL-C• CRP (vs. Met. Synd.)• Lp(a)• Microalb’uria, GFR• Hcy• RLP-C • LpPLA2 (PLAC)Arterial Tests (1o Prev)• CAC by CT• Carotid US• Ankle Brachial Index (SBP
ankle/SBP arm <.9)
Why?
• Rx yes/no?
• More aggressive Rx?
• Specific Rx
When?
• 1o Prevention
– Intermediate-Risk
• 2o Prevention, CVD:
– W/ normal lipid profile
– Severe beyond risk factors
– Progression despite “adequate” Rx
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Combination Therapy Statin + Other Med
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18
9.9
1314.4
11.29.4
7.9
16.6
0
5
10
15
20
25
% ofpatients
100 101- 111- 121- 131- 141- 151- >160 110 120 130 140 150 160
LDL-C (mg/dL) on-treatment
n = 1,460
L-TAP: Majority of CHD Patients
Do Not Reach NCEP LDL-C Goal
Pearson TA et al. Arch Intern Med. 2000;160:459-467.Other L-TAP data courtesy of TA Pearson.
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Statin dose (mg)
LD
L-C
Example of Statin Titration and Failureto Attain Optimal LDL-C
Starting LDL-C 220 mg, 40% Lowering at Statin 10 mg
Optimal50
100
150
200
250
0 20 40 60 80 100
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20 mg includes pts on 40 mg (37%). This does not represent data from a comparative study. Data from prescribing information for atorvastatin, lovastatin, simvastatin.
Statin Titration: Potential for Side Effects at Maximum Dose
20 40 8010 20 40 800
0.5
1.0
1.5
2.0
2.5
Ele
vate
d t
ran
sam
inas
es(%
of
pat
ien
ts)
8040
1.7 4
2.3
20
Statin dose (mg)
Atorvastatin Lovastatin Simvastatin
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More vs. Less Aggressive LDL-C Lowering Rx
Study LDL-C LowRx
LDL-C HiRx
Add'lLDL↓
Add’lCHD↓
Safety
Prove-IT 95 mg/dl 62 mg/dl 35% 16% 3x ↑ALT
A to Z 81 mg/dl 66 mg/dl 18% 11% 9x ↑myop*
TNT 101 mg/dl 77 mg/dl 24% 22% 6x ↑ALT
IDEAL 103 mg/dl 82 mg/dl 20% 11% 2x ↑myalg 9x ↑ALT
Prove-IT: Prava 40 vs. Atorva 80. NEJM, 2004;350:1495-1504.A to Z: Simva 20 vs. Simva 80. JAMA, 2004;292:1307-1316.TNT: Atorva 10 vs. Atorva 80. NEJM, March 8, 2005.IDEAL: Simva 20-40 vs. Atorva 80. JAMA 2005; 294:2437-2445.
*Included patients w/ ARF, EtOH abuse and on meds interfering w/ statin metabolism.
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Majority of CAD Events Occur Despite Statin Rx:
Need for Further Rx Improvement
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383.
28
19
0
5
10
15
20
25
30
% w
ith
CA
D e
ven
t 30% ↓CAD w/ statin
70% CAD events not prevented
CAD Events in the 4S Trial
Placebo Simvastatin
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-100
-80
-60
-40
-20
0
Event Reduction With Monotherapy Versus Combination Therapy
-31 -36
ASCOT19341
WOSCOPS 6595
FATS (10 Y)176
4S 4444
Trial N
-72
-34 -25
HPS20,536
Red
uct
ion
in C
V
Eve
nts
(%
)
CARE4159
-24
1. Shepherd J, et al. N Engl J Med. 1995;333:1301-1307; 2. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; 3. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009; 4. HPS Collaborative Group. Lancet. 2002;360:7-22; 5. Sever PS, et al. Lancet. 2003;361:1149-58; 6. Brown BG, et al. Circulation. 1998;98(suppl I):I-635.
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3.9
-0.4
0.7
23.7
2.6
14.3
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Placebo S+N S+N+AV
HATS: Angiographic and Clinical Endpoints After 3 Years
Coronary Death, MI, Stroke, or Revascularization
Mea
n C
han
ge
in S
ten
osi
s, % C
om
po
site Even
t Rate, %
9 Proximal Lesions
25
20
15
10
5
0
*p<0.001 vs. placebo; †p<0.005 vs. placebo; ‡p=0.04 vs. placebo.Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592.
HATS = HDL-C-Atherosclerosis Treatment Study; S = simvastatin; N = niacin; AV = antioxidant vitamins.
*
†
‡
89% reduction
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PlaceboNiacin ER 1g/d
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Ezetimibe + Atorvastatin 10 mg: Greater LDL-C Reduction vs. Atorvastatin 20 or 40 mg Alone
–54%
–45%–42%
–37%
–53%–60%
–50%
–40%
–30%
–20%
–10%
0%
Mean %Change in LDL-C
FromUntreated Baseline
P<0.01
Ezetimibe +Atorvastatin 10 mg
(n=65)10 mg(n=60)
20 mg(n=60)
40 mg(n=66)
80 mg(n=62)
Atorvastatin
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-46.1-44.3
-50.2-49.1
-55.6-52.5
-59.4
-37.2
-60
-50
-40
-30
-20
-10
0
% R
edu
cti
on
fro
mb
ase
line
at
wk
6
Ezetimibe/simvastatinAtorvastatin10 20 80 10/10 10/20 10/40 10/8040
**PP0.0010.001 vs atorvastatin at corresponding dose. vs atorvastatin at corresponding dose.
Ballantyne et al.Ballantyne et al. J Am Coll CardiolJ Am Coll Cardiol. 2004;43(suppl A):480A.. 2004;43(suppl A):480A.
**
**
Ezetimibe/Simvastatin vs. Atorvastatin Ezetimibe/Simvastatin vs. Atorvastatin LDL-C LoweringLDL-C Lowering
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Ezetimibe With Fenofibrate in Hypercholesterolemia
-13.5
-22.3
-36.3
-10.1
-40
-35
-30
-25
-20
-15
-10
-5
0
Placebo(n=8)
Fenofibrate 200 mg(n=8)
Ezetimibe 10 mg(n=8)
Ezetimibe 10 mg +fenofibrate 200 mg(n=8)
Mea
n %
LD
L-C
re
du
ctio
n a
fter
14
d
†
*Ezetimibe is not yet indicated for combination use with fenofibrate or any other non-statin lipid agent. †P<0.03 vs placebo or either drug alone.Kosoglou et al. European Atherosclerosis Society Meeting, Glasgow, Scotland, 2001.
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Statin Mono Rx vs. Combination Rx
Favoring Combo Rx
• Better LDL-C lowering
• Better non-LDL effects (HDL-C, TG, CRP, other?)
• Likely better CVD event reduction
• Complementary mechanisms
Favoring Statin Mono Rx
• Nearly comparable LDL-C↓ (esp. w/ rosuva.)
• Simpler (less AE risk)
• Less expensive (esp. rosuva.)
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Atheroprevention in Postmenopausal Women
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Incidence of Cardiovascular Events in Women Before and After the Menopause
Incidence of Cardiovascular Events in Women Before and After the Menopause
0
50
100
150
200
250
300
350
Inci
den
ce /
100
,000
Inci
den
ce /
100
,000
20-2420-24 25-2925-29 30-3430-34 35-3935-39 40-4440-44 45-4945-49 50-5450-54 55-5955-59 60-6460-64 >65>65
Age RangeAge RangeF. B. Hu et al. New Engl J Med, 2000; 343:530-7F. B. Hu et al. New Engl J Med, 2000; 343:530-7
Average Age Average Age at Menopauseat Menopause
In postmenopausal women, atherosclerosis is a disease of estrogen deficiencyIn postmenopausal women, atherosclerosis is a disease of estrogen deficiency
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Risk of Cardiac Events/Death in Estrogen Users in 6 Large Observational Studies
0.00.0 0.50.5 1.01.0 1.51.5 2.02.0
Relative Risks andRelative Risks and 95%Confidence Intervals95%Confidence Intervals
Bush, T. L. et al., Lipid Research ClinicsFollow-up Study Circulation 75:1102, 1987Bush, T. L. et al., Lipid Research ClinicsFollow-up Study Circulation 75:1102, 1987
Grodstein, F. et al., Nurses Health StudyN Engl J Med 335:453, 1996Grodstein, F. et al., Nurses Health StudyN Engl J Med 335:453, 1996
Criqui, M. H. et al., Rancho Bernardo Study Am J Epidemiol 128:606, 1988Criqui, M. H. et al., Rancho Bernardo Study Am J Epidemiol 128:606, 1988
Falkeborn, M. et al., Uppsala Health Care Region Br J Obstet Gynaecol 99: 821, 1992Falkeborn, M. et al., Uppsala Health Care Region Br J Obstet Gynaecol 99: 821, 1992
Hunt, K. et al., British Menopausal Hormone Study Br J Obstet Gynaecol 97:1080, 1990*Hunt, K. et al., British Menopausal Hormone Study Br J Obstet Gynaecol 97:1080, 1990*
Psaty, B. M. et al. Group Health Cooperative of Puget Sound Arch Intern Med 154:1333, 1994Psaty, B. M. et al. Group Health Cooperative of Puget Sound Arch Intern Med 154:1333, 1994
*Deaths from circulatory diseases*Deaths from circulatory diseases
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Rationale for the Randomized HRT Trials
(HERS&WHI)
• Supposed to verify observational studies:–peri-menopausal start
• Instead studied– late post-menopausal start
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
1 2 3 4 5 6+
Pe
rce
nt
CH
D E
ve
nts
*
CEE/MPA
Placebo
HazardYear Ratio
1 1.78
2 1.15
3 1.06
4 0.99
5 2.38
6+ 0.78
Year
WHI: Percent CHD Events by Year
P = NS for trend over time.
HR = 1.29
95% nCI = 1.02–1.63
95% aCI = 0.85–1.97
*Includes 8 silent MIs.
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
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Early vs. Late Estrogen Effects on the Natural History of Atherosclerosis
Adventitia
Media
Fatty Streak/Plaque
InternalElastic
Lamina
Necrotic Core
Plaque
FibrousCap
FibrousCap
Plaque Necrotic Core
Plaque
FibrousCap
MMP-9
•Estrogen Effects in Atherogenesis LDL oxidation LDL atherogenicity LDL binding/accum lesion progression CAMs monocyte adhesion/
macrophage accumulation
MCP-1 and TNF SMC proliferation lesion progression Endothelial function vasodilation
•Estrogen Effects in Established Plaques MMP expression PQ instability/rupture Thrombosis Event # and severity
•Loss of Estrogen Benefits (when HRT started after prolonged estrogen deficiency) Expression of estrogen receptors Vascular responsivity
Benefits of estrogen early in atherogenesis
Adverse effects ofestrogen in vulnerable plaque
CAMs = cell adhesion molecules; SMC = smooth muscle cell; MMP = matrix metalloproteinase.
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1Clarkson TB, et al. J Clin Endocrinol Metab. 1998;83:721-6. 2Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997;17:217-21. 3Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-7. 4Williams JK, et al. Arterioscler Thromb Vasc Biol. 1995;15:827-36.
Premenopause Postmenopause
Ovariectomy
70%Decrease1,2Healthy diet CEE + atherogenic diet
Plaque Area(Relative to Placebo)
50%Decrease3
Atherogenic diet
CEE + atherogenic diet
0%No change4
Healthy dietAtherogenic diet+ No CEE 2 years
Healthy Diet+ CEE
Timing of CEE Start vs. Anti-atherosclerosis Effect
(Nonhuman Primates)
***
*Like Obs. HRT trials
**Like HERS/WHI
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0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
2.6R
isk
Rat
io f
or
CV
D
0 5 10 15 20 25 30Years Postmenopause at Randomization
<10
10-19
≥ 20
*Data from Manson, et al. New Engl J Med, 2003;349:530 (Fig. 3)*Data from Manson, et al. New Engl J Med, 2003;349:530 (Fig. 3)
Zero-YearRR=0.62
Timing of HRT Start vs. Effects on CVD: Extrapolation of WHI Results (E+P Arm)
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Nurses’ Health Study, 1980-1996
NeverNever
0.3 mg*0.3 mg*
0.625 mg*0.625 mg*
1.25 mg1.25 mg
1.01.0
0.580.58 (0.37-0.92) (0.37-0.92)
0.540.54 (0.44-0.67) (0.44-0.67)
0.70 (0.51-0.97)0.70 (0.51-0.97)
609609
1919
9999
4141
Hormone Use
Multivariate-adjustedRR (95% CI)
Cases(n)
Person-years of Follow-up
Grodstein F, et al. Ann Intern Med. 2000;133:933-41.
313,661313,661
19,96419,964
116,150116,150
39,02639,026
RR = relative risk for current vs. never users.
Effect of Estrogen Dose on Risk for CHD
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Nurses’ Health Study, 1980-1996
NeverNever
0.3 mg*0.3 mg*
0.625 mg*0.625 mg*
1.25 mg1.25 mg
1.01.0
0.540.54 (0.28-1.06) (0.28-1.06)
1.351.35 (1.08-1.68) (1.08-1.68)
1.63 (1.18-2.26)1.63 (1.18-2.26)
290290
99
124124
4646
Hormone Use
Multivariate-adjustedRR (95% CI)
Cases(n)
Person-years of Follow-up
Grodstein F, et al. Ann Intern Med. 2000;133:933-41.
313,661313,661
19,96419,964
116,150116,150
39,02639,026
RR = relative risk for current vs. never users.
Effect of Estrogen Dose on Risk for Stroke
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“Because of the excellent study design of WHI there is now consensus that CEE+MPA should not be started in older women to prevent heart disease.”—Good for <10% of ERT
“Whether benefit would be seen if women initiated hormones …at… menopause was not addressed in the WHI.” —Nothing learned about >90% of ERT(!)
“We need new clinical trials to test the hypothesis not addressed by the WHI—that younger women who initiate hormones…at the time their own estrogen levels drop will eventually…have less heart disease.” —KEEPS under way
ML Stefanick, Kronos Longevity Kronicle 2004;3(7);6-11.
What to do while we await relevant RCT data? Choice A: Use best current evidence which is: early-start, long-term/lifetime
ERT/HRT benefits most women!Choice B: D/C ERT/HRT (assume WHI applies to all women)
WHI Scorecard: $600M Later…
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HRT in Postmenopausal Women:
State of the Art 2005• HRT is good in most women
– All perimenopausal women should be considered for HRT (early start) esp if estr. defic Sx present
– Low-dose oral CEE/MPA usually best (if tolerated); – Oral or patch estradiol are good alternatives– Continue life-long (unless/until adverse event—VTE, etc.)
• Current dogma (D/C of HRT after 1-5 y) is likely harmful • Late-start HRT usually bad
Caveat: HRT does not have FDA indication for CHD prevention
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Factor Statins BAS CAI Fibrates Niacin
↓LDL-C +++ ++ ++ +/- ++
↑LDL size - ? ? ++ ++
↓TG ++ - + +++ ++
↓Remnant ++ - ++? +++ +++
↓Lp(a) - ? ? +/- +++
↑HDL + +/- + +/++ +++
Lipoprotein Effects of Major Lipid Rx Classes:
Summary