Lipid Management
Standard and Advanced
Preview of ATP-IV
Thomas G. Allison, PhD, MPH
Mayo Clinic
Rochester, MN
USA
DISCLOSURE
Relevant Financial Relationship(s)
None
Off Label Usage
None
Treatment Categories, LDL-C Goals and
Cut-points: ATP-III
Risk Category
CHD or
CHD risk equivalent
2 Risk Factors
10-yr risk 10–20%
10-yr risk <10%
<2 Risk Factors
LDL-C Goal
Consider Drug
Therapy
<100 mg/dL
130 mg/dL*
<130 mg/dL
<130 mg/dL
130 mg/dL
160 mg/dL
<160 mg/dL
190 mg/dL
* 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy
Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Major ATP III Risk Factors
• Age
Male ≥ 45 years
Female ≥ 55 years
• Family History
Male first degree relative < 55 years
Female first degree relative < 65 years
• HDL-C < 40 mg/dL
• Hypertension
• Current Smoking
CAD Equivalents
•
•
•
•
•
•
•
Coronary Artery Disease (CAD)
Diabetes Mellitus
Abdominal Aortic Aneurysm
Carotid Artery Disease (>50% stenosis)
Prior CVA or TIA
Peripheral Arterial Disease
Framingham Score >20% 10 yr Risk
CAD Risk Equivalents?
• Chronic Renal Insufficiency
• Abnormal Coronary Calcium Scores
– Agatston score > 400
Goals for Therapy: 2004 Addendum
•
NCEP ATP III guidelines for LDL Therapy
LDL-C <160 for 1 or less risk factors
LDL-C <130 for 2+ risk factors
< 100 is a therapeutic option
LDL-C <100 for CAD and CAD equivalents
<70 is option for very high risk patients
1.
2.
3.
4.
5.
CAD + multiple risk factors, especially diabetes
CAD + severe or poorly controlled risk factor(s)
CAD + metabolic syndrome
Acute coronary syndrome
CAD event despite baseline LDL-C < 100
LDL-C Therapy
•
•
•
•
•
•
Lifestyle Change
Statins
Bile Acid Sequestrants
Ezetimibe
Niacin
Plant Stanols, Sterols, Phytosterols
Residual Risk: Non-HDL-C
• ATP III: Non-HDL-C is a secondary target
of drug therapy when TG ≥ 200mg/dL
• Represents all the triglyceride-rich
lipoproteins – considered atherogenic
• Non-HDL-C = Total Cholesterol – HDL-C
• Valid even if patient is non-fasting
• Cost-Effective
Targets for Therapy after LDL-C Goal in
Patients with TG 200 mg/dL
LDL-C target
(mg/dL)
Non-HDL-C
target (mg/dL)
CHD or CHD risk
equivalent
<100
<130
No CHD, 2+ RF
<130
<160
No CHD, <2 RF
<160
<190
Patient Category
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-2497.
Potential Goal Modifying Factors
• Lp(a)
• High sensitivity CRP
• Metabolic Syndrome
Definition of the Metabolic Syndrome
Defined by presence of >3 risk factors
Risk Factor
Defining Level
Waist circumference (abdominal obesity)
>40 in (>102 cm) in men
>35 in (>88 cm) in women
Triglyceride level
>150 mg/dl
HDL-C level
<40 mg/dl in men
<50 mg/dl in women
Blood pressure
>130/>85 mmHg
Fasting glucose
>100 mg/dl
Grundy, et al. Diagnosis and management of the metabolic syndrome: an
AHA/NHLBI Scientific Statement. Circulation 2005;112:2735-2752.
Dr. Allison Attempts to Call
Forth the Contents of ATP-IV
Will ATP-IV Signal a New Wave of
Lipid Management?
Sweeping Changes?
Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults
(Adult Treatment Panel IV)
Expert Panel Membership
Co-Chairs
Alice H. Lichtenstein, D.Sc.
Tufts University
Boston, Massachusetts
Neil Stone, M.D.
Northwestern University School of Medicine
Chicago, Illinois
C. Noel Bairey Merz, M.D.
University of California, Los Angeles
Daniel Rader, M.D.
University of Pennsylvania
Conrad Blum, M.D.
Columbia University
Jennifer Robinson, M.D, M.P.H.
University of Iowa
Robert H. Eckel, M.D.
University of Colorado, Denver
Frank M. Sacks, M.D.
Harvard University
School of Public Health
Anne Carol Goldberg, M.D., FACP, FAHA
Washington University
J. Sanford Schwartz, M.D.
University of Pennsylvania
Ronald M. Krauss, M.D.
Children's Hospital Oakland
Research Institute
Sidney C. Smith, Jr. M.D.
University of North Carolina
Donald M. Lloyd-Jones, M.D., Sc.M.
Northwestern University
Karol Watson, M.D., Ph.D.
University of California at Los Angeles
Patrick McBride, M.D., M.P.H.
University of Wisconsin
Peter W. F. Wilson, M.D.
Emory University School of Medicine
Status
Expected Availability for Public Review
and Comment: Spring 2011
Expected Release Date: Fall 2011
Issues for ATP-IV
1. Should the goals for LDL-C in primary
prevention be lowered?
2. What to do with CRP – routine use in risk
stratification, secondary target?
3. What about secondary target?
–
Non-HDL-C, HDL-C, apo B, LDL Particle
concentration?
4. Move from 10-year to lifetime risk?
Jupiter Trial
• To test the hypothesis that statin treatment
will reduce CV events in patients without
baseline CVD with “normal” LDL-C (< 130
mg/dL) and elevated hsCRP (≥ 2.0 mg/L)
Ridker PM et al. NEJM 2008;359:2195-2207
• The most innovative and potentially
important lipid-lowering trial since the 2004
ATP-II Addendum
Jupiter Methods
• 17,802 subjects (38% women)
– Men ≥ 50 years; women ≥ 60 years
– Triglycerides < 500 mg/dL
• Randomized to Rosuvastatin 20 mg/day or
placebo
• Planned 60 month follow-up
• Primary outcome was major CV event
– Including elective revascularization
Jupiter Results
• Study terminated early on 3-30-08 with
median follow-up of 1.9 years
• Compliance at study termination was 75%
• 44% reduction in primary endpoint
– 0.77% versus 1.36% per year
• 20% reduction in total mortality
– 1.00% versus 1.25% per year
12-Month Laboratory Results
(Medians)
Rosuvastatin
Placebo
hs-CRP
2.2
3.5
LDL-C
55
110
HDL-C
52
50
TG
99
119
JUPITER Questions
• Would a lower-cost, generic statin show
similar benefit?
• Is measurement of hsCRP necessary for risk
stratification in primary prevention
– Ridker conflict of interest issues
• Was the benefit due to LDL-C lowering or
hsCRP lowering?
Risk Factors in Jupiter Subjects
•
•
•
•
•
•
Average age = 66 years
Current smokers = 16%
Metabolic syndrome = 41%
Family history of premature CAD = 11%
25% had fasting glucose > 102 mg/dL
25% had systolic BP > 145 mmHg
PROVE IT - TIMI 22:
Study Design
4,162 patients with an Acute Coronary Syndrome < 10 days
ASA + Standard Medical Therapy
Double-blind
“Standard Therapy”
Pravastatin 40 mg
“Intensive Therapy”
Atorvastatin 80 mg
2x2 Factorial: Gatifloxacin vs. placebo
Duration: Mean 2 year follow-up (>925 events)
Primary Endpoint: Death, MI, Documented UA requiring hospitalization,
revascularization (> 30 days after randomization), or Stroke
Changes from (Post-ACS)
Baseline in Median LDL-C
LDL-C
(mg/dL)
120
Median LDL-C (Q1, Q3)
100
95 (79, 113)
Pravastatin 40mg
80
21%
62 (50, 79)
60
49% 
Atorvastatin 80mg
40
P<0.001
20
<24h Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final
Note: Changes in LDL-C may differ from prior trials:
• 25% of patients on statins prior to ACS event
• ACS response lowers LDL-C from true baseline
PROVE IT:
Concomitant Therapies
PCI for initial ACS pre-random.
69%
Aspirin
93%
Warfarin
8%
Clopidogrel (initial)
(at F/U)
72%
20%
B-blockers
85%
ACE
69%
ARB
14%
All-Cause Death or Major CV Events
in All Randomized Subjects
30
Pravastatin 40mg
(26.3%)
25
20
%
with 15
Event
Atorvastatin 80mg
(22.4%)
16% relative risk reduction
(p = 0.005)
10
5
But absolute residual risk is 22%
0
0
3
6
9
12
15
18
21
Months of Follow-up
24
27
30
Sources of Residual Risk
• Not providing appropriate medical therapy?
• Inadequate control of non-lipid risk factors?
• Not addressing emerging risk factors?
– CRP, Lp(a)
• Inadequate control of lipids using LDL target
only?
–
–
–
–
–
Non-HDL
HDL or apo A-1
Apo B
LDL particle number
LDL particle size
Secondary Lipid Target
• In ATP-III, non-HDL-C was identified as
the secondary lipid target
– Sum of cholesterol in all atherogenic
lipoproteins
• LDL-C, Lp(a)-C, VLDL-C, IDL-C
• No major trial since publication of ATP-III
in 2001 that specifically treated non-HDL-C
Lowering non-HDL-C
•
•
•
•
•
Increase the statin dose
Add fibrate
Add niacin
High dose fish oil
Exercise, CHO restriction, weight loss
FIELD Study
Fenofibrate to Prevent Cardiovascular Events
in Diabetics
FIELD Study Investigators Lancet 2005; 366:1849-1861
FIELD Mortality
No significant benefit shown in ACCORD-Lipids
for fenofibrate added to Simvastatin 40 mg/day.
NEJM 2010, March 14.
LDL Particles Cause
Atherosclerosis
Low Density Lipoprotein
particles (LDL) are the causal
agents in atherosclerosis.1
The more LDL particles a person has, the higher
the risk for plaque buildup that causes heart
attacks, regardless of how much cholesterol
those particles carry.
1 Fredrickson et al. NEJM 1967; 276: 148
LDL-C is not LDL
Apo B
POLAR
SURFACE COAT
Phospholipid
Free cholesterol
This is LDL
NONPOLAR
LIPID CORE
Cholesterol Ester
Triglyceride
This is LDL
Cholesterol
James Otvos 2007
lipoproteins
EDTA
sugars
LDL Particle Number Distribution in MESA
LDL-C <100 mg/dL (n=1,425)
5th
25
10%
(n=141)
20th
42%
(n=603)
50th
80th percentile
36%
(n=509)
10%
(n=150)
2%
(n=22)
20
Percent
of
Subjects
15
10
5
0
700
1000
1300
1600 (nmol/L)
LDL Size (nm)
21.3 (0.7)
20.5 (0.6)
20.1 (0.5)
HDL-C (mg/dL)
58 (18)
47 (15)
41 (11)
Triglycerides (mg/dL)
98 (60)
136 (71)
199 (75)
AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006
LDL Particle Number Distribution in MESA
LDL-C = 100-118 mg/dL
5th
25
1%
(n=10)
20th
24%
(n=215)
50th
54%
(n=484)
80th
19%
(n=168)
percentile
3%
(n=26)
20
Percent
of
Subjects
15
22%
10
MetSyn (-)
(n=903)
5
0
700
25
20
0%
(n=0)
1000
4%
(n=20)
1300
33%
(n=153)
1600 (nmol/L)
46%
(n=210)
15
Percent
of
Subjects
17%
(n=76)
63%
MetSyn (+)
(n=459)
10
5
0
700
1000
1300
AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006
1600 (nmol/L)
Probability of Event-free Survival
CHD Event Associations of NMR LDL Particle
Number (LDL-P) versus LDL Cholesterol (LDL-C)
Low LDL-C – Low LDL-P
(n=1249)
High LDL-C – Low LDL-P
(n=284)
High LDL-C – High LDL-P
(n=1251)
Low LDL-C – High LDL-P
(n=282)
Years of Follow-up
Cromwell WC et al: J Clinical Lipidology 2007;1:583-592
Brief Comments
Apo B or Non-HDL versus LDL-P
• Apo B and non-HDL are likely better
predictors of risk than LDL-C in patients
with cardiometabolic syndrome
• Non-HDL costs nothing extra to measure
• Apo B measurement does not require
unique, expensive technology
• Apo B gives equal weight to each particle:
LDL, Lp(a), VLDL, IDL
– Not equal atherogenicity
– Treatment strategies different for each particle
• Non-HDL similarly lumps particle types
together
Example 1
– TC=200, HDL=50, TG=200, non-HDL=150
Example 2
– TC=170, HDL=20, TG=500, non-HDL=150
• Is risk equivalent for these 2 patients?
Prediction of Lifetime Risk for
Cardiovascular Disease by Risk
Factor Burden at 50 Years of Age
Donald M. Lloyd-Jones et al
Circulation 2006;113:791-798
Generic Prevention Drugs
Drug
Monthly Cost
Statin
$4.00
Beta blocker
$4.00
Metformin
$4.00
ACE-inhibitor ± HCTZ $4.00
Amlodipine
$4.00
All national discount pharmacy chains
– Lower price ($10) for 3 months supply
Can potentially reduce cost further with a pill cutter
Living Under
the Umbrella of
Good
Cardiovascular
Health
LDL-C
FBG
SBP
<100
<100
<120
Predictions for ATP-IV
1. The goals for LDL-C in primary prevention will
be lowered.
2. There will be a stronger statement on hsCRP, but
routine use in risk stratification or use as
secondary target will not be specifically
endorsed.
3. Non-HDL-C will remain the secondary lipid
target, but optional use of apo B or LDL-P will
be endorsed.
4. A new risk calculator providing lifetime risk
estimates will be provided.
• Comments?
• Questions?