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UPDATE ON MANAGEMENT OF ATHEROGENIC DYSLIPIDEMIA OF
INSULIN RESISTANCE, OBESITY, AND TYPE 2 DIABETES:
BEYOND LDL CHOLESTEROL
Ronald M. Krauss, MD
Children’s Hospital Oakland Research Institute
UC Berkeley and UCSF
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Atherogenic Dyslipidemia in Obesity, Insulin Resistance, and Metabolic Syndrome
High triglyceride (TG) levels TG-rich remnant lipoproteins (VLDL) Altered metabolism of LDL and HDL particles
Absolute levels of LDL cholesterol are commonly not significantly increased, number of LDL particles Predominantly small, dense LDL particles
Low levels of HDL cholesterol (may reduce reverse cholesterol transport)
Adapted from Haffner SM Diabetes Care 2003; 26: S83-6and Garvey WT et al. Diabetes 2003; 52: 453-62
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Metabolic Basis for Atherogenic Dyslipidemia: Concordant Increase in VLDL and Small LDL and Reduction of HDL
SmallerLDL
HL
Apo AI
Renalclearance
LPL
RemnantsLPL/HL
VLDL
TG TG CETP
Cholesterol
HDL
TGTGLDL
TGTG SmallerHDL
Apo AI: apolipoprotein AI
CETP: cholesteryl ester transfer protein
HL: hepatic lipase
LPL: lipoprotein lipase
TG: triglycerides
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Residual Cardiovascular Risk in Major Statin Trials
Reprinted from J Am Coll Cardiol, Vol 46, Libby P. The forgotten majority: Unfinished business in cadiovascular risk reduction, 1225-8, Copyright © 2005, with permission from Elsevier
LDLN 4,444 4,159 20,536 6,595 6,6059,014
-36% -28% -29% -26% -27%-25%
Secondary High risk Primary
Pat
ien
ts e
xper
ien
cin
g
maj
or
coro
nar
y ev
ents
(%
)
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Re
lati
ve
CV
D r
isk
†
Triglyceride Level is an Independent Cardiovascular Disease (CVD) Risk Factor – Meta-Analysis of 17 Studies
Adapted from Austin MA et al. Am J Cardiol 1998; 81: 7B-12B
Men (n=22,293)
Women (n=6,345)
Men (n=46,413)
Women (n=10,864)
*
*
*
*
†Associated with an 89 mg/dl (1.00 mmol/l) increase in triglycerides
*p<0.05
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Triglyceride Level Remains a Cardiovascular Disease (CVD) Risk Factor in Patients Treated With Statins - CARE and LIPID
Adapted from Sacks FM et al. Circulation 2000; 102: 1893-900
CV
D e
ven
t ra
te*
Placebo
Pravastatin
<98 99-126 127-158 159-207 >207
Triglyceride levels (mg/dl)
Slope=0.018p=0.02
Slope=0.029p<0.001
n=13,173
*Coronary heart disease death, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty
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Coronary Heart Disease (CHD) Risk: HDL Cholesterol vs. LDL Cholesterol as Predictor*
Adapted from Castelli WP Can J Cardiol 1988; 4 (Suppl A): 5A-10A
*Data represent men aged 50 – 70 from the Framingham Heart StudyR
elat
ive
risk
of
CH
D a
fter
4 y
ears
LDL cholesterol (mg/dl)
8565
4525
HDL
cholesterol
(mg/dl)
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Statin Therapy Does Not Eliminate Cardiovascular Disease (CVD) Risk Associated With Low HDL Cholesterol
Adapted from HPS Collaborative Group Lancet 2002; 360: 7-22and Sacks FM et al. Circulation 2000; 102: 1893-900
CARE: Cholesterol and Recurrent Events
HPS: Heart Protection Study
LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease
CV
D e
ven
t ra
te (
%)
High HDL cholesterol + statin
Low HDL cholesterol + statin
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Relative Risk of Myocardial Infarction (MI) According to Triglycerides (TG) and HDL Cholesterol: Case-Control Study in CAD Patients
Adapted from Gaziano et al. Circulation 1997; 96: 2520-5
Quartiles of TGQuartiles of TG, adjusted for HDL cholesterolQuartiles of log TG/HDL cholesterol
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Apo B
Similar LDLcholesterol
Slower plasma clearance Greater artery uptake & retention Faster oxidation More particles
Cholesterylester
LDL Cholesterol Underestimates the Number of LDL Particles When Levels of Small LDL Are Increased
Larger LDL (phenotype A)More cholesterol/particle
Smaller LDL (phenotype B)Less cholesterol/particle
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Favourable Shift in LDL Particle Size is Strongly Associated With End-of-Treatment Triglyceride (TG) Values
Adapted from Davidson MH et al. Clin Cardiol 2006; 29: 268-73
Med
ian
in
crea
se i
n L
DL
par
ticl
e d
iam
eter
(n
m)
TG level† (mg/dl)
<200 200-299 ≥300 Ch
ang
e f
rom
bas
elin
e (%
)
TG
*
Small LDL cholesterol
Large LDL cholesterol
LDL particle concentration
*
*
TG† <200 mg/dl
TG† ≥200 mg/dl
†End-of-treatment TG level
*p<0.03 vs. TG level ≥200 mg/dl
Triglyceride reduction in metabolic syndrome (TRIMS)
Significant inverse relationshipp value for trend =0.019
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Pharmacologic Options for Management of Atherogenic Dyslipidemia
LDL lowering: statin, ezetimibe, resin
Triglyceride reducing, HDL raising: niacin, fibrates, omega-3 fatty acids
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Coronary Drug Project: Niacin Effects on 6-Year Cardiovascular Disease (CVD) and 15-Year Mortality
Reprinted from Am J Cardiol, Vol 95, Canner PL et al. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug
Project), 254-7 Copyright © 2005, with permission from Elsevier
CHD: coronary heart disease
MI: myocardial infarction
Hazardratio
0.83 0.71 0.84 0.86p<0.005 p<0.005 p<0.005 p<0.05
Niacin
Placebo
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Coronary Drug Project: Niacin Effects on 6-Year Nonfatal Myocardial Infarction by Fasting Plasma Glucose
Reprinted from Am J Cardiol, Vol 95, Canner PL et al. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug
Project), 254-7 Copyright © 2005, with permission from Elsevier
<95 95-104 105-125 ≥126
Fasting plasma glucose (mg/dl)
Hazardratio
0.70 0.76 0.75 0.43
Niacin
Placebo
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ADVENT: Safety of Niacin for Dyslipidemia Associated With Type 2 Diabetes
Reprinted from Arch Intern Med, Vol 162, Grundy SM et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial), 1568-76
Copyright © 2002, with permission from Elsevier
*
Baseline Week 4 Week 8 Week 12 Week 16
n=148
*p=0.048 vs. placebo
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Primary Prevention With Gemfibrozil The Helsinki Heart Study
Adapted from Manninen V et al. Circulation 1992; 85: 37-45
Inci
den
ce
of
car
dia
c e
ven
tsp
er
1,0
00 p
ers
on
-ye
ars
0
5
10
15
20
HDL cholesterol 42 HDL cholesterol 42
TG 200 TG 200 TG 200 TG 200mg/dl
Gemfibrozil
TG: triglycerides
Placebo
Incidence of coronary heart disease events
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VA-HIT: Gemfibrozil Effect on Primary Endpoint - Lipids
Adapted from Rubins HB et al. N Engl J Med 1999; 341: 410-8
LDL cholesterol TG
HDL cholesterol
Primary endpoint occurrence*†
Ch
ang
e fr
om
bas
elin
e (%
)
%
Placebo Gemfibrozil
*Nonfatal myocardial infarction or death from coronary causes
†22% relative risk reduction (95% CI: 7%–35%, p=0.006)
TG: triglycerides
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VA-HIT: LDL and HDL Particle Subclasses Are Favourably Affected by Fibrate Treatment
Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63
IDL: intermediate-density lipoprotein
B: baseline
Placebo Fibrate
5% reduction
13641463
1352 1290*
LD
L p
arti
cle
nu
mb
er (
nm
ol/l
)
B 7 months B 7 months
20
% d
ec
rea
se
36
% i
nc
rea
se
*
*
HD
L p
arti
cle
nu
mb
er (m
ol/l
) 25.2 25.126.6 27.6*
Placebo Fibrate
B 7 months B 7 months
21
% i
nc
rea
se
*
*
10% increase
*p≤0.0005 vs. placebo at 7 months
IDL Large HDL Large LDL Medium HDL Small LDL Small HDL
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Rel
ativ
e o
dd
s ra
tio
†
LDL particle number
LDL particle size
**
Rel
ativ
e o
dd
s ra
tio
†
HDL particle number
HDL particle size
**
VA-HIT: LDL and HDL Particle Numbers Are Significant, Independent Predictors of New Coronary Heart Disease Events
Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63
Baseline
7 months
†Calculated for a 1-SD increment of each lipoprotein particle in separate logistic regression models adjusted for treatment group, age, hypertension, smoking, body mass index, and diabetes
*p<0.05
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VA-HIT: Cardiovascular Disease Risk Reduction in Nondiabetic Patients
Adapted from Rubins HB et al. Arch Intern Med 2002; 162: 2597-604
Ris
k re
du
ctio
n
≤23
n=434
24-29 30-38 ≥39
n=431n=426n=442
Quartiles of fasting plasma insulin (µU/ml)
Fav
ou
rs g
emfi
bro
zil
Fav
ou
rs p
lace
bo
p=0.04 vs. placebo
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Myocardial Infarction Prevention With Bezafibrate in Metabolic Syndrome
Reprinted from Arch Intern Med, Vol 165, Tenenbaum A et al. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome, 1154-60
Copyright © 2005, with permission from Elsevier
0
Myo
card
ial
infa
rcti
on
(%
)
Car
dia
c m
ort
alit
y (%
)
Time (years) Time (years)
Log-rank p=0.02 Log-rank p=0.07
5
10
15
20
0
5
10
15
PlaceboBezafibrate
1 2 3 4 5 6 7 8 901 2 3 4 5 60
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Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)
Subjects: 9,795 (37% female) patients with type 2 diabetes aged 50-75 years with and without coronary heart disease (CHD)
Entry lipid criteria: cholesterol = 116-251 mg/dl (3.00-6.50 mmol/l), plus either Cholesterol/HDL cholesterol ratio >4
or Triglycerides >89 mg/dl (1.00 mmol/l)
Treatment: fenofibrate 200 mg once daily or placebo for 5 years
Primary endpoint: CHD death plus nonfatal myocardial infarction
Adapted from Keech AC and the FIELD Study Investigators Cardiovasc Diabetol 2004; 3: 9-24
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FIELD: End of Study Lipid Results
Adapted from Keech A et al. Lancet 2005; 366: 1849-61
Placebo (P)Fenofibrate (F)
113
LDLcholesterol
HDLcholesterol
Triglycerides
Baseline (mg/dl)
117 43 43 164 167
119
LDLcholesterol
HDLcholesterol
Triglycerides
Baseline (mg/dl)
119 43 43 171 173
128
LDLcholesterol
HDLcholesterol
Baseline (mg/dl)
125 42 40 184 197
Triglycerides
Did not start other lipid-lowering therapyn= 3,124 (P) 3,951 (F)
Total population
Started other lipid-lowering therapyn= 1,776 (P) 944 (F)
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Ev
ent
rate
(%
)
FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events*
Adapted from Keech A et al. Lancet 2005; 366: 1849-61
11% reductionp=0.16
*Nonfatal myocardial infarction or CHD death
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24% reductionp=0.01
19% increasep=0.22
FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events*
Adapted from Keech A et al. Lancet 2005; 366: 1849-61
PlaceboFenofibrate
*Nonfatal myocardial infarction or CHD death
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FIELD Primary Prevention Population: Effects on Coronary Heart Disease (CHD) Events and Total Cardiovascular Disease (CVD) Events
Adapted from Keech A et al. Lancet 2005; 366: 1849-61
Ris
k re
du
ctio
n (
%)
(n=7,664) (n=7,664)
p=0.014
p=0.004
CHD events Total CVD
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FIELD: Microvascular Disease
Adapted from Keech A et al. Lancet 2005; 366: 1849-61
Progression RegressionP
ati
en
ts (
%)
P F P F
14% reductionp<0.001
30% reductionp=0.0003
Placebo Fenofibrate
Pa
tie
nts
(%
)
*Progression of albuminuria was defined as the proportion of patients who progressed either from normoalbuminuria to microalbuminuria or from microalbuminuria to macroalbuminuria.
Placebo (P)Fenofibrate (F)
Laser treatment for retinopathy Progression and regression of albuminuria*
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FIELD: Clinically Important Adverse Events
Adverse EventPlacebo, %
n=4,900
Fenofibrate, %
n=4,895
Newly diagnosed cancer 7.6 8.0
Deep-vein thrombosis 1.0 1.4
Pulmonary embolism 0.7 1.1‡
Pancreatitis 0.5 0.8§
Myositis* 0.02 0.04
Rhabdomyolysis† 0.02 0.06
Renal disease requiring dialysis 0.4 0.3
ALT 3-5x ULN 0.5 0.2
>5x ULN 0.2 0.2
CPK 5-10x ULN 0.1 0.2
>10x ULN 0.06 0.08
Creatinine increase >2.26 mg/dl 1.0 1.5
ALT: alanine aminotransferase
CPK: creatine phosphokinase
ULN: upper limit of normal
*Myositis was experienced by 1 placebo and 2 fenofibrate patients†Rhabdomyolysis was experienced by 1 placebo and 3 fenofibrate patients (none were taking a statin)‡p=0.022§p=0.031
Adapted from Keech A et al. Lancet 2005; 366: 1849-61
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Pharmacologic Options for Atherogenic Dyslipidemia
LDL lowering: statin, ezetimibe, resin
Triglyceride reducing, HDL raising: niacin, fibrates; omega-3 fatty acids
Combination therapy
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SAFARI: Combination Therapy in Patients With Combined Hyperlipidemia
Reprinted from The American Journal of Cardiology, Vol 95, Grundy SM et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial), 462-8
Copyright © (2005), with permission from Elsevier
**
*
*Simvastatin 20
Simvastatin 20 + Fenofibrate 160
n=618
*p<0.001 vs. simvastatin
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SAFARI: Effects on LDL Particle Subclasses
Adapted from Grundy SM et al. Am J Cardiol 2005; 95: 462-8Reproduced with permission
Simvastatin +Fenofibrate
Simvastatin Simvastatin
Ch
an
ge
fro
m b
ase
line
in
LD
L p
att
ern
(%
)
Baseline Week 12*
Incr
ease
d p
arti
cle
siz
e
n=618
*Significantly different pattern between the 2 treatment groups (p<0.001)
B (Smaller, dense)
AB (Intermediate)
A (Larger, buoyant)
Simvastatin +Fenofibrate
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Atorvastatin and Fenofibrate Alone or in Combination in Patients With Type 2 Diabetes
Adapted from Athyros VG et al. Diabetes Care 2002; 25: 1198-202
TriglyceridesLDL
cholesterolHDL
cholesterol
Ch
an
ge
fro
m b
ase
line
(%
)
*
*
*
*‡
*
*
*†
Atorvastatin 20 mgFenofibrate 200 mgCombination
*†
n=120
*p <0.0001 vs. baseline
†p <0.05 vs. both monotherapies
‡p <0.05 vs. atorvastatin
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Statin-Fibrate Combination Therapy: Pharmacokinetic Interactions
Adapted from:
TriCor [package insert]. Abbott Laboratories; 2004
Kyrklund C et al. Clin Pharmacol Ther 2001; 69: 340-5
Pan W J et al. J Clin Pharmacol 2000; 40: 316-23
Backman JT et al. Clin Pharmacol Ther 2000; 68: 122-9
Backman JT et al. Clin Pharmacol Ther 2002; 72: 685-91
Abbott Laboratories. Data on file; 2005
Davidson MH Am J Cardiol 2002; 90 (suppl): 50K-60K
Prueksaritanont T et al. Drug Metab Dispos 2002; 30: 1280-7
Martin PD et al. Clin Ther 2003; 25: 459-71
Bergman AJ et al. J Clin Pharmacol 2004; 44: 1054-62
Gemfibrozil Fenofibrate
Atorvastatin Expected in Cmax No effect
Simvastatin Cmax by 2-fold No effect
Pravastatin Cmax by 2-fold No effect
Rosuvastatin Cmax by 2-fold No effect
Fluvastatin No effect No effect
Lovastatin Cmax by 2.8-fold Not available
Cerivastatin Cmax by 2-3-fold No effect
Cmax: maximum concentrations
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Effects of Lovastatin or Lovastatin and Niaspan on Lipid Parameters
Adapted from Hunninghake DB et al. Clin Cardiol 2003; 26: 112-8
Ch
an
ge
fro
m b
ase
line
(%
)
LDL cholesterol
HDL cholesterol
Triglycerides
Lovastatin 40 mg
Lovastatin 20 mg + 1,000 mg niaspan (Advicor)
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Analysis of the HDL-Atherosclerosis Treatment Study (HATS): Angiographic and Clinical Endpoints After 3 Years – Simvastatin + Niacin vs. Placebo
Adapted from Brown BG et al. N Engl J Med 2001; 345: 1583-92
Placebo
Mea
n c
han
ge
in s
ten
osi
s (%
)
*p<0.001 vs. placebo
‡p=0.04 vs. placebo
Coronary death, myocardial infarction, stroke or
revascularization
Simvastatin + Niacin
Co
mp
osite even
t rate (%)
3.923.7
-0.4
2.6*‡
89% reduction
-0.5
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Nine proximal lesions
25
20
15
10
5
0
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ARBITER 2: Statin Plus Placebo vs. Statin Plus Extended-Release Niacin (ERN)
12 monthsP value
BL vs. 12 months
Lipid (mg/dl)Statin +Placebo
Statin + ERN
P Value
Statin +Placebo
Statin + ERN
n 71 78
LDL cholesterol 86 20 85 25 NS NS NS
HDL cholesterol 40 9 47 16 0.003 NS <0.001
Triglycerides 164 83 134 87 0.03 NS 0.009
Non-HDL cholesterol
115 21 107 34 NS 0.03 0.02
Values are mean SD BL: baseline
Adapted from Taylor AJ et al. Circulation 2004; 110: 3512-7
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ARBITER 2: Statin + Placebo vs. Statin + Extended-Release Niacin 1,000 mg/d Primary Endpoint – Carotid Intima-Media Thickness (CIMT) Change
Adapted from Taylor AJ et al. Circulation 2004; 110: 3512-7
Statin + Placebo(n=71)
Statin + Extended release niacin
(n=78)
Bas
elin
e C
IMT
(m
m)
Ch
ang
e in
CIM
T (
mm
)Statin + Extended
release niacin(n=78)
p=0.23*
Statin + Placebo(n=71)
p<0.001*
*Within-group comparisons
Baseline CIMT after 1 year
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Kaplan-Meir Estimates of Incidence of Coronary Events on Patients Receiving Statin or Statins and Omega-3 Fatty Acid (EPA)
Reprinted from The Lancet, Vol 369, Yokoyama M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis, 1090-98
Copyright © 2007, with permission from Elsevier
All patients Primary prevention
Secondary prevention
18,645 Japanese (70% women, 61 years) randomized to statin alone or statin + EPA (1.8 g/d) and followed for 5 years
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