“Lipidology (Pre ATP-IV):
Everything I Can Discuss on What You
Should Know”
How to Prevent a Heart Attack
June 12, 2010
Robert H. Eckel, M.D.
Professor of Medicine
Division of Endocrinology, Metabolism and Diabetes
Division of Cardiology
Professor of Physiology and Biophysics
Charles A. Boettcher II Chair in Atherosclerosis
University of Colorado Denver School of Medicine
Director Lipid Clinic, University Hospital
The Lipid Patient
Five Groups
•  LDL cholesterol
•  TG ( HDL cholesterol
•  LDL cholesterol +  TG
•  HDL cholesterol
•  Lipoprotein (a)
Assessing Acquired Causes of
Dyslipidemia
• Lifestyle
– Diet, inactivity, alcohol, tobacco
• Medications
– Steroids, diuretics, -blockers, PIs, cis-RA
•
•
•
•
Insulin resistance
Thyroid disease
Liver disease
Kidney disease
– Proteinuria
–  GFR
Revised NCEP ATP III LDL-C Goals
CHD Risk
Category
High
(Very High)
Moderately High
Moderate
Low
Circulation 110:227, 2004
CHD or Risk
Equivalent
(>20%/10 yrs)
2+ RF
(10-20%/10 yrs)
2+ RF
(<10%/10 yrs)
0–1 RF’s
LDL-C
Goal
Consider
Drug Rx
<100
100*
(<70)
<130
130*
<130
160*
<160
190*
* Consider drug options if below goal,
but above goal for next higher risk level
Revised NCEP ATP III Non-HDL
Goals
CHD Risk
Category
High
(Very High)
Moderately High
Moderate
Low
Circulation 110:227, 2004
Non-HDL-C Consider
Goal
Drug Rx
CHD or Risk
Equivalent
(>20%/10 yrs)
2+ RF
(10-20%/10 yrs)
2+ RF
(<10%/10 yrs)
0–1 RF’s
<130
130*
(<100)
<160
160*
<190
190*
<190
190*
* Consider drug options if below goal,
but above goal for next higher risk level
NHLBI Clinical Guidelines for CVD Risk Reduction:
Organizational Structure
NHLBI Director
Guideline
Leadership
Group
DARD Director
SAIC Support
Contract
DARD Project
Team
Clinical Guidelines Executive Committee
Cross-Cutting Workgroups
Risk Assessment
Lifestyle/Nutrition/PA
Implementation/System/IT/
Informatics
Expert Panel
for the
Integrated CVD
Guideline
Development
Expert Panel
for
Cholesterol
Updates
Expert Panel
for
Hypertension
Updates
Expert Panel
for Obesity
Updates
Major Lipids, Apolipoproteins and CVD Risk:
The Emerging Risk Factors Collaboration
• 302,430 people without CVD from 68
long-term prospective studies
– Mostly Europe and North America
• 2.79 million person-years of follow-up
– 8857 non-fatal MIs
– 3928 CHD deaths
– 2534 ischemic strokes
– 513 hemorrhagic strokes
– 2536 unclassified strokes
ERF Collaboration, JAMA 302:1993, 2009
CHD Risk: Non-HDL vs. HDL
Cholesterol
(n = 302,430)
ERF Collaboration, JAMA 302:1993, 2009
Apolipoprotein B
 One apo B molecule/particle
 Assesses potentially atherogenic


particle number
Helps to distinguish risk of CHD in
patients with hypertriglyceridemia
Highly correlated with non-HDL
cholesterol
• 0.95 when TG < 300 mg/dl
• 0.80 when TG higher
Apo B May Predict Vascular Events
Better than LDL Cholesterol
• Observational studies
– Quebec Cardiovascular Study
– LIPID (placebo)
– AMORIS
• Interventional studies
–
–
–
–
AFCAPS/TexCAPS (lovastatin)
LIPID (pravastatin)
IDEAL (simvastatin, atorvastatin)
TNT (atorvastatin)
CHD Risk Based on Lipids
and Apolipoproteins
(n = 91,307)
ERF Collaboration, JAMA 302:1993, 2009
The real value of apo B
is in patients without
increases in LDL
cholesterol, in patients
with
hypertriglyceridemia
Impact of TG Levels on Relative Risk
of CHD: Framingham Heart Study
3.0
2.5
Men
Women
2.0
RR 1.5
1.0
0.5
0.0
50
100
150
200
250
300
350
400
TG
(mg/dL)
Castelli WP. Can J Cardiol. 4:5A, 1988
Hypertriglyceridemia (1 mM ) and
CHD: A Meta-Analysis (21 studies)
Relative Risk
MEN (65,863):
WOMEN (11,089):
1.30 (1.25-1.35)
1.69 (1.45-1.97)
Adjusted for HDL cholesterol (9 studies):
MEN (29,105):
1.17 (1.10-1.26)
WOMEN (6,345):
1.37 (1.13-1.66)
Abdul-Maksoud M and Hokanson J.E., J Vasc Med, 2001
Risk of CHD in the Top vs. Bottom Tertile of
Usual Log-TG by Study Characteristics
Sarwar, N. et al. Circulation 2007;115:450-458
Sarwar N et al, Circulation 115:450, 2007
Apo B and CHD Risk: MetaAnalysis
Thompson A and Danesh J, Journal of Internal Medicine, 259:481, 2006
CHD and Ischemic CVA Risk: Emerging Risk
Factors Collaboration Meta-Analysis
CHD
(n = 302,430 people)
CVA
ERF Collaboration, JAMA 302:1993, 2009
Odds Ratios for the Development of CHD:
Lipid and Lipoprotein Phenotypes
Odds are adjusted for age, smoking, alcohol, blood pressure,
gender, and medications
(0.005) (0.001)
3.1
2.7
(0.01)
2.1
(0.001)
2.8
OR
1.7
1.0
1.0
Normal IIA
IIB
IV
Nl TG  TG  HDL
HyperapoB
Lamarche B et al, Am J Card 75:1189, 1995
Management of  Triglycerides
Goal: Is it TG?
No, it’s non-HDL cholesterol!
Then isn’t it TG < 150 mg/dl?
Or should it be apo B?
Correlations Between Apo B, Cholesterol, LDL
Cholesterol and Non-HDL Cholesterol
Sniderman AS et al, Am J. Card 91:1173, 2003
ACC/ADA Lipid Goals
CHD or
DM + 1
Risk
Factor
≥ 2 Risk
Factors
or DM
LDL-C
NonHDL-C
Apo B
< 70
mg/dl
< 100
mg/dl
< 80
mg/dl
< 100
mg/dl
< 130
mg/dl
< 90
mg/dl
Brunzell JD et al, JACC 51:1512, 2008
LDL-C Reduction in Statin Trials
35
Clinical statin trial data
iEmax model, r2 = 0.82, p=0.01
30
4S P
Event Rate (%)
25
20
4S Tx
15
10
TNT 80 mg
CARE Tx
HPS Tx
LIPID P
CARE P
HPS P
TNT 10 mg
LIPID Tx
5
0
0
25
50
75
100
125
150
175
200
LDL-C (mg/dL)
Charland SL, et al. Circulation 2005; 112:II-816
Statins: The Down Side
• Abnormal AST and ALT
– < 3X ULN: ~1.3%
– > 3X ULN: <1.0%
• Dose related
• Myopathy: Any disease of muscles
– Myalgias: pain in a muscle of group of muscles
• ~10%
– Myositis: muscle symptoms with  CK
• ~2.5%
– Rhabdomyolysis: > 50 fold  in CK + renal impairment
• <0.1%
Bruckert E et al, Cardiov Drugs 19:403, 2005
Brown WV, Curr Opin Lipid 19:558, 2008
Onusko E, J Fam Pract 57:449, 2008
What the Clinician Needs to
Consider
• Hypothyroidism
• Other drugs
– Fibrates, azole anti-fungals, cyclosporine,
macrolides, diltiazem, HIV protease inhibitors
• Genetic differences in drug-metabolizing
enzymes, e.g. OATP1B1
– SLCO1B1, CYP2D2, 3A4
• Neuromuscular diseases
– Mitochondrial myopathy, McArdles disease,
myotonic dystrophy, polymyositis
Patient Types
Diagnostic Strategies
CK in high risk patients only
Asymptomatic
CK measured:
< 5 x normal
Moderate to
Severely
Symptomatic
Stop Statin:
CK measured,
hydrate if
creatinine ↑
Eckel RH, JCEM In Press, 2010
Titrate Statin Dose to
reach LDL and nonHDL-C goals
Ezetimibe
and/or BAS
Symptoms worse:
repeat CK &
Stop or Reduce
Statin Dose
Mildly
Symptomatic
Therapeutic Options
Symptoms
gone:
CK ↓&
creat↓
Fluvastatin or
pravastatin,
20 mg per night or
every other night
Fluvastatin XL
80 mg per night
Rosuvastatin 5 mg
daily, every other day,
or weekly
Red yeast rice,
600-1800 bid
LIPOSORBER® SYSTEM
LIPOSORBER® SYSTEM
Re-Priming
Solution
Heparin Pump
Regeneration
Solution
Regeneration
Pump
Blood Pump
Plasma Pump
Plasma
Separator
Blood Return
LIPOSORBER®
Columns
Plasma Line
Waste Line
LIPOSORBER® SYSTEM
LDL-C
Diet Therapy
Diet & Drug Therapy
LIPOSORBER® Treatment
Pre
Time Average
Post
Time
LIPOSORBER® SYSTEM
LONG TERM EFFICACY OF LDL APHERESIS
ON CHD IN Familial Hypercholesterolemia
Patients
Heterozygous FH with CHD
Treatment
LDL-Apheresis and Medication (n = 43)
(Average LDL-Apheresis Interval = 14 days)
Medication Only (n = 87)
Follow-Up
6 Year Observation of Coronary Events
(Non-Fatal MI, PTCA, CABG, CHD Death)
Results
72% reduction in Coronary Events for apheresis patients
Mabuchi H et al. Am J Card 82:1489, 1998
What about nonstatin approaches in
the reduction of LDL
cholesterol and
CHD?
Maintain an Overall Healthy Diet!
Dietary Patterns and MI Risk in
52 Countries: INTERHEART
5761 cases
10,646 controls
Iqbal R et al, Circulation 118:1929, 2008
Dietary Risk Score (7 components) and
MI Risk in 52 Countries: INTERHEART
Range of LDL Cholesterol
Lowering with Drugs
•
•
•
•
•
Statins
15-60%
Bile Acid Sequestrants 5-35%
Ezetimibe
15-20%
Fibrates
10-25%
Nicotinic acid
0-20%
Randomized Intervention Trials: Relationship
Between LDL-C Reduction and Major Coronary
Secondary
Events
30
prevention
trials
Primary
prevention
trials
4S
HPS
25
Major
coronary
event rate
(%)
20
LIPID
15
LRC-CPPT
CARE
10
Post-CABG
5
WOSCOPS
AFCAPS/
TexCAPS
0
60
80
100
120
140
160
180
200
LDL-C during trial (active treatment and placebo)
Modified from Waters DD and Azar RR. Am J Cardiol. 86:35J-43J, 2000.
Fox R. Circulation. 2001;104:e9051; Schwartz GG et al. JAMA. 285:1711, 2001
Where are we at on
ezetimibe?
ARBITER 6-HALTS
• “HALTS”: HDL And LDL Treatment Strategies
• Purpose
– Compare the effectiveness of combination lipid
lowering therapy with either extended-release niacin or
ezetimibe added to long-term statin therapy for the
endpoint of carotid intima-media thickness over 14
months
• PROBE Design
– Prospective, randomized, parallel-group, open-label
study involving blinded evaluation of endpoints
• Walter Reed Army Medical Center- Washington, D.C.
• Washington Adventist Hospital- Takoma Park, MD
Overall Baseline Characteristics
•
•
•
•
N = 208
80% male
Age: 65 ± 11 years
All on statins
– 42 ± 25 mg/d
– 6 ± 5 years duration
– 95% simvastatin or
atorvastatin
Baseline measured variables
• TC
147 ± 26 mg/dL
• LDL-C
82 ± 23 mg/dL
• HDL-C
42 ± 8.5 mg/dL
• TG
134 ± 68 mg/dL
• CIMT
– Mean
– Max
0.8977 ± 0.1583 mm
1.0179 ± 0.1653 mm
•Baseline characteristics balanced in the 2 treatment groups.
•Baseline statin dose: Little room for additional statin titration.
Results: Lipid Concentrations
Niacin
Niacin
• Niacin: HDL
increased by 18.4%
to 50 mg per
deciliter
• LDL and TG
• Ezetimibe: LDL
decreased by
19.2%, to 66 mg
per deciliter
P < 0.001
Ezetimibe
P = 0.01
Ezetimibe
Niacin
Ezetimibe
P = 0.001
P = 0.01
Niacin
Ezetimibe
Δ LDL-C
Δ HDL-C
Δ TG (median)
Ezetimibe
−17.6±20.1 mg/dL
−2.8±5.7 mg/dL
-9 mg/dL
Niacin
−10.0±24.5 mg/dL
+7.5±9.2 mg/dL
-36 mg/dL
Results: Primary Endpoint
Between-group Change in CIMT
• Niacin was superior
to ezetimibe for the
primary endpoint of the
between group
difference in carotid
intima-media thickness.
•P = 0.003
Results: LDL Change vs. CIMT Change
•
In a post hoc analysis, we explored the bivariate relationships between changes
in LDL cholesterol levels and mean carotid intima–media thickness.
•
Ezetimibe
R = -0.31; P < 0.001
•
Niacin
R = -0.01; P = 0.92
Posted online at www.nejm.org
•
Paradoxical increase
in CIMT in patients
treated with
ezetimibe with
greater reductions in
LDL cholesterol.
This effect was not
observed with
niacin.
Hypothesis
generating regarding
the net effects of
ezetimibe’s complex
mechanism of action
in patients with
dyslipidemia.
Results: Major CVD Events
Major adverse cardiovascular events occurred at a significantly lower incidence in
the niacin (2/160 patients [1.2%] vs. the ezetimibe group (9/165 patients [5.5%])
•Chi-square p=0.04; Log-rank p = 0.047
HDL:
So what do we
really know?
HDL and Atherosclerosis
• Anti-oxidant
• Anti-inflammatory
• Anti-thrombotic
–  prostacyclin
• Promotes vascular reactivity
–  NOS
• Reverse cholesterol transport
The HDL Proteome
PLTP
CETP
LCAT ApoC-I
ApoC-II
ApoM
ApoC-III
ApoF
SERF2
AGT
SERF1
ApoC-IV
ApoE
Lipid Metabolism
ApoD
Proteinase
Inhibitor
PON3
SAA4
ApoL-1
SAA2
ApoA-II
Clusterin
ApoA-IV ApoH PON1
Complement
Regulation
SAA1
ApoA-I
HRP
AHSG
SERA1
AMP
KNG1
Acute Phase Response
C3
C4A
C4B
C9
VTN
ORM2
TTR
ITIH4 RBP4 TF
FGA
HPX
Vaisar T et al. J Clin Invest. 117:746, 2007
HDL- Paradox
• CETP deficient Japanese families with HDL levels
• 80-100 mg/dL or higher in heterozygotes
• But, possibly an increase in CHD risk
• Apo A1Milano
• Low HDL octagenarians with low CHD risk
• Tangier Disease
• ABCA1 gene deficiency
• Genetically low HDL: Turkey (HTGL gene mutation) and
China
• When relocated to an urban environment,  CHD risk
• Many patients without low HDL have CHD
• Pro-inflammatory HDL?
• Type 1 diabetes
Novel Therapies for Raising HDL
•
•
•
•
•
•
Reconstituted HDL
Apo A-1
Apo A-1 Milano
Apo A-1 peptides
PPAR-/ dual agonists
New drug classes
For HDL, where’s
the evidence?
Coronary Drug Project
15-Year Mortality Results
Niacin Placebo
Risk
n=1,119 n=2,789 Reduction
Total Mortality
P
52%
58%
-11%
<0.005
FBG < 100 mg/dL
48%
53%
-9%
<0.05
FBG  100 mg/dL
56%
63%
-12%
<0.005
36%
41%
-12%
<0.01
CHD Mortality
Canner PL et al, J Am Coll Cardiol. 8:1245, 1986.
% of Patients with Non Fatal MI
CDP - METABOLIC SYNDROME
Placebo
n = 124
Niacin
30
25
20
69% 
15
28% 
10
5
0
Metabolic Syndrome (+)
Metabolic Syndrome (-)
Canner PL et al, Am J Cardiol. 2006 97:477, 2006
CDP - METABOLIC SYNDROME
% of Patients (Total Mortality)
Placebo
n = 368
Niacin
80
70
60
27% 
17% 
50
40
30
20
10
0
Metabolic Syndrome (+)
Metabolic Syndrome (-)
Canner PL et al, Am J Cardiol. 2006 97:477, 2006
Niacin and CVD Events in the Metabolic
Syndrome: FATS, HATS, AFREGS
Zhao XQ et al, Am J Cardiol. 104:1457, 2009
Definitive HDL Cholesterol
Outcome Studies
• HPS2-Thrive
– This study is currently recruiting participants.
– Verified by University of Oxford, November
2009
– First Received: April 17, 2007 Last Updated:
November 4, 2009 History of Changes
– Purpose - The primary aim is to assess the
effects of raising HDL cholesterol with
extended release niacin/laropiprant vs.
matching placebo on the risk of MI or coronary
death, stroke, or the need for revascularization
in people with a history of circulatory problems.
Definitive HDL Cholesterol
Outcome Studies
• Aim High
– Plaque Inflammation and Dysfunctional HDL
Cholesterol in Participants Receiving Niacin and Statins
in the AIM-HIGH Study (The HDL Proteomics Study)
– This study is currently recruiting participants.
– Verified and funded by National Heart, Lung, and Blood
Institute (NHLBI), April 2009
– First Received: April 10, 2009 No Changes Posted
– Purpose: This study will examine MRI images and
blood samples of participants who are taking niacin
plus statins or statins alone to determine the effect of
these medications on inflammation in atherosclerotic
plaques.
IMPROVE-IT
• IMPROVE-IT:
– Examining Outcomes in Subjects With Acute Coronary
Syndrome: Vytorin (Ezetimibe/Simvastatin) vs.
Simvastatin (Study P04103AM3) – clinicaltrials.gov
– This study is currently recruiting participants.
– First Received: September 13, 2005 Last Updated:
December 10, 2009 History of Changes
– Primary Outcome: To measure the effect of treatment
with ezetimibe/simvastatin compared with simvastatin
monotherapy on death due to any CVD events, nonfatal coronary events (i.e. MI), and non-fatal strokes.
• Time Frame: Trial will continue until a minimum of 5,250
subjects have a primary endpoint event and each subject is
followed for a minimum of 2.5 years.
New Non-Statin Therapies for
Atherogenic Lipoprotein Lowering
• MTP inhibitors
• Antisense apolipoprotein B
• Thyroid hormone -receptor
agonists
– Pro-drug targeted to the liver
• PCKSK9 inhibitors
Lipoprotein (a):
What do We Know?
Lipoprotein (a) Genotype, Level
and CHD Risk
Clarke R et al, NEJM 361:2518, 2009
The Lipid Patient:
Lipoprotein (a) > 30 mg/dl
LDL cholesterol Goal
– <160, <130, <100, <70 mg/dl
• NCEP-ATP:III
– <145, <115, <85, <55 mg/dl
• Suggested goal for
lipoprotein (a) > 30 mg/dl
So What are the Tough
Decisions?
Question
My Opinion
LDL-C: How low?
Statin Intolerance
<100 or < 70
Your choice
LDL-C: What drugs?
All if needed
TG, Non-HDL-C or Apo B
in Patients with  TG?
HDL-C: A target for Rx?
Lipoprotein (a)?
Apo B
????
> 30 mg/dl,  LDL-C by
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