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Lipid ManagementStandard and Advanced
Preview of ATP-IV
Thomas G. Allison, PhD, MPH
Mayo Clinic
Rochester, MN
USA
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DISCLOSURERelevant Financial Relationship(s)
None
Off Label UsageNone
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Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Treatment Categories, LDL-C Goals and Cut-points: ATP-III
Risk Category LDL-C GoalConsider Drug
Therapy
CHD or CHD risk equivalent <100 mg/dL 130 mg/dL*
2 Risk Factors
10-yr risk 10–20%
10-yr risk <10%<130 mg/dL
<130 mg/dL
130 mg/dL
160 mg/dL
<2 Risk Factors <160 mg/dL 190 mg/dL
* 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy
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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
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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
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CAD Risk Equivalents?
• Chronic Renal Insufficiency
• Abnormal Coronary Calcium Scores– Agatston score > 400
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Goals for Therapy: 2004 Addendum• NCEP ATP III guidelines for LDL Therapy
LDL-C <160 for 1 or less risk factorsLDL-C <130 for 2+ risk factors
< 100 is a therapeutic optionLDL-C <100 for CAD and CAD equivalents
<70 is option for very high risk patients1. CAD + multiple risk factors, especially diabetes2. CAD + severe or poorly controlled risk factor(s)3. CAD + metabolic syndrome4. Acute coronary syndrome5. CAD event despite baseline LDL-C < 100
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LDL-C Therapy
• Lifestyle Change
• Statins
• Bile Acid Sequestrants
• Ezetimibe
• Niacin
• Plant Stanols, Sterols, Phytosterols
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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
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Targets for Therapy after LDL-C Goal in Patients with TG 200 mg/dL
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Patient CategoryLDL-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
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Potential Goal Modifying Factors
• Lp(a)
• High sensitivity CRP
• Metabolic Syndrome
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Grundy, et al. Diagnosis and management of the metabolic syndrome: an AHA/NHLBI Scientific Statement. Circulation 2005;112:2735-2752.
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
Definition of the Metabolic SyndromeDefinition of the Metabolic Syndrome
Defined by presence of >3 risk factors
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Dr. Allison Attempts to Call Forth the Contents of ATP-IV
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Will ATP-IV Signal a New Wave of Lipid Management?
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Sweeping Changes?
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Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel IV)
Expert Panel Membership
Co-ChairsAlice H. Lichtenstein, D.Sc.
Tufts UniversityBoston, Massachusetts
Neil Stone, M.D.Northwestern University School of Medicine
Chicago, Illinois
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C. Noel Bairey Merz, M.D.University of California, Los Angeles
Conrad Blum, M.D.Columbia University
Robert H. Eckel, M.D.University of Colorado, Denver
Anne Carol Goldberg, M.D., FACP, FAHAWashington University
Ronald M. Krauss, M.D.Children's Hospital Oakland
Research Institute
Donald M. Lloyd-Jones, M.D., Sc.M.Northwestern University
Patrick McBride, M.D., M.P.H.University of Wisconsin
Daniel Rader, M.D.University of Pennsylvania
Jennifer Robinson, M.D, M.P.H.University of Iowa
Frank M. Sacks, M.D.Harvard University
School of Public Health
J. Sanford Schwartz, M.D.University of Pennsylvania
Sidney C. Smith, Jr. M.D. University of North Carolina
Karol Watson, M.D., Ph.D.University of California at Los Angeles
Peter W. F. Wilson, M.D.Emory University School of Medicine
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Status
Expected Availability for Public Review and Comment: Spring 2011
Expected Release Date: Fall 2011
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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?
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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)
• The most innovative and potentially important lipid-lowering trial since the 2004 ATP-II Addendum
Ridker PM et al. NEJM 2008;359:2195-2207
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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
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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
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12-Month Laboratory Results (Medians)
Rosuvastatin Placebo
hs-CRP 2.2 3.5
LDL-C 55 110
HDL-C 52 50
TG 99 119
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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?
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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
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4,162 patients with an Acute Coronary Syndrome < 10 days 4,162 patients with an Acute Coronary Syndrome < 10 days
ASA + Standard Medical Therapy
“Standard Therapy”Pravastatin 40 mg
“Intensive Therapy”Atorvastatin 80 mg
Duration: Mean 2 year follow-up (>925 events)
Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
PROVE IT - TIMI 22: Study Design
2x2 Factorial: Gatifloxacin vs. placebo
Double-blindDouble-blind
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Changes from (Post-ACS) Baseline in Median LDL-C
Note: Changes in LDL-C may differ from prior trials: Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event25% of patients on statins prior to ACS event• ACS response lowers LDL-C from true baselineACS response lowers LDL-C from true baseline
LDL-C (mg/dL)
20
40
60
80
100
120
Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final
Pravastatin 40mg
Atorvastatin 80mg49% 49%
21%21%
P<0.001P<0.001
Median LDL-C (Q1, Q3)Median LDL-C (Q1, Q3)
95 (79, 113)95 (79, 113)
62 (50, 79) 62 (50, 79)
<24h
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PROVE IT:Concomitant Therapies
PROVE IT:Concomitant Therapies
PCI for initial ACS pre-random. 69%
Aspirin 93%
Warfarin 8%
Clopidogrel (initial) 72% (at F/U) 20%
B-blockers 85%
ACE 69%
ARB 14%
PCI for initial ACS pre-random. 69%
Aspirin 93%
Warfarin 8%
Clopidogrel (initial) 72% (at F/U) 20%
B-blockers 85%
ACE 69%
ARB 14%
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All-Cause Death or Major CV Events in All Randomized Subjects
00 33 1818 2121 2424 2727 303066 99 1212 1515
% with
Event
Months of Follow-up
Pravastatin 40mgPravastatin 40mg(26.3%)(26.3%)
Atorvastatin 80mgAtorvastatin 80mg(22.4%)(22.4%)
16% relative risk reduction16% relative risk reduction
(p = 0.005)(p = 0.005)
3030
2525
2020
1515
1010
55
00
But absolute residual risk is 22%
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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
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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
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Lowering non-HDL-C
• Increase the statin dose
• Add fibrate
• Add niacin
• High dose fish oil
• Exercise, CHO restriction, weight loss
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FIELD Study Fenofibrate to Prevent Cardiovascular Events
in Diabetics
FIELD Study Investigators Lancet 2005; 366:1849-1861
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FIELD Mortality
No significant benefit shown in ACCORD-Lipidsfor fenofibrate added to Simvastatin 40 mg/day.
NEJM 2010, March 14.
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LDL Particles Cause Atherosclerosis
Low Density Lipoprotein
particles (LDL) are the causal
agents in atherosclerosis.1
1 Fredrickson et al. NEJM 1967; 276: 148
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.
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This is LDLThis is LDLCholesterolCholesterol
This is LDLThis is LDL NONPOLARNONPOLARLIPID CORELIPID CORE
Cholesterol EsterCholesterol Ester TriglycerideTriglyceride
POLARPOLARSURFACE COATSURFACE COAT
PhospholipidPhospholipidFree cholesterolFree cholesterol
Apo BApo B
LDL-C is not LDL
James Otvos 2007
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EDTA
sugars
lipoproteins
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0
5
10
15
20
2542%
(n=603)
Percentof
Subjects
10%(n=141)
5th 20th 50th 80th percentile
700 1000 1300 1600 (nmol/L)
36%(n=509)
10%(n=150)
2%(n=22)
LDL Particle Number Distribution in MESA
LDL-C <100 mg/dL (n=1,425)
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
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0
5
10
15
20
25
700 1000 1300 1600 (nmol/L)
4%(n=20)
33%(n=153)
46%(n=210)
17%(n=76)
Percentof
Subjects
0%(n=0)
0
5
10
15
20
25 24%(n=215)
Percentof
Subjects
1%(n=10)
5th 20th 50th 80th percentile
MetSyn (-)
(n=903)
700 1000 1300 1600 (nmol/L)
54%(n=484)
19%(n=168)
3%(n=26)
MetSyn (+)(n=459)
LDL Particle Number Distribution in MESALDL-C = 100-118 mg/dL
63%
22%
AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006
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CHD Event Associations of NMR LDL Particle Number (LDL-P) versus LDL Cholesterol (LDL-C)
Pro
babi
lity
of E
vent
-fre
e S
urvi
val
Years of Follow-up
Low LDL-C – High LDL-P(n=282)
High LDL-C – High LDL-P(n=1251)
High LDL-C – Low LDL-P(n=284)
Low LDL-C – Low LDL-P(n=1249)
Pro
babi
lity
of E
vent
-fre
e S
urvi
val
Years of Follow-up
Low LDL-C – High LDL-P(n=282)
High LDL-C – High LDL-P(n=1251)
High LDL-C – Low LDL-P(n=284)
Low LDL-C – Low LDL-P(n=1249)
Pro
babi
lity
of E
vent
-fre
e S
urvi
val
Years of Follow-up
Low LDL-C – High LDL-P(n=282)
High LDL-C – High LDL-P(n=1251)
High LDL-C – Low LDL-P(n=284)
Low LDL-C – Low LDL-P(n=1249)
Pro
babi
lity
of E
vent
-fre
e S
urvi
val
Years of Follow-up
Low LDL-C – High LDL-P(n=282)
High LDL-C – High LDL-P(n=1251)
High LDL-C – Low LDL-P(n=284)
Low LDL-C – Low LDL-P(n=1249)
Cromwell WC et al: J Clinical Lipidology 2007;1:583-592
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Brief CommentsApo 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
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• 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 togetherExample 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?
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Prediction of Lifetime Risk for Cardiovascular Disease by Risk
Factor Burden at 50 Years of AgeDonald M. Lloyd-Jones et al
Circulation 2006;113:791-798
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Generic Prevention DrugsDrug Monthly CostStatin $4.00Beta blocker $4.00Metformin $4.00ACE-inhibitor ± HCTZ $4.00Amlodipine $4.00
All national discount pharmacy chains– Lower price ($10) for 3 months supply
Can potentially reduce cost further with a pill cutter
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Living Under the Umbrella of
Good Cardiovascular
Health
FBG<100
LDL-C<100 SBP
<120
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Predictions for ATP-IV1. 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.
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• Comments?
• Questions?