Lipid ManagementStandard and Advanced

Preview of ATP-IV

Thomas G. Allison, PhD, MPH

Mayo Clinic

Rochester, MN

USA

DISCLOSURERelevant Financial Relationship(s)

None

Off Label UsageNone

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

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 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

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

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

Potential Goal Modifying Factors

• Lp(a)

• High sensitivity CRP

• Metabolic Syndrome

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

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-ChairsAlice H. Lichtenstein, D.Sc.

Tufts UniversityBoston, Massachusetts

Neil Stone, M.D.Northwestern University School of Medicine

Chicago, Illinois

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

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)

• The most innovative and potentially important lipid-lowering trial since the 2004 ATP-II Addendum

Ridker PM et al. NEJM 2008;359:2195-2207

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

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

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

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%

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%

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-Lipidsfor 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

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.

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

EDTA

sugars

lipoproteins

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

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

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

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

• 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?

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

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

Living Under the Umbrella of

Good Cardiovascular

Health

FBG<100

LDL-C<100 SBP

<120

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.

• Comments?

• Questions?