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pre-program survey in your packet. Your pre-program survey in your packet. Your participation will help us assess participation will help us assess the effectiveness of this program the effectiveness of this program and shape future CME activities.and shape future CME activities.

CVD RISK REDUCTION AND LIPID MANAGEMENTState of the Science in HDL Therapy

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future educational needs.future educational needs.

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Thank you.Thank you.

CVD RISK REDUCTION AND LIPID MANAGEMENTState of the Science in HDL Therapy

Faculty DisclosuresFaculty Disclosures

• The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:

• Presenter, MD: Research: Pharma Company; Consultant: Pharma Company

TO BE FILLED IN BY PRESENTING PHYSICIAN(S)

Steering Committee DisclosuresSteering Committee Disclosures

The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:

•Robert S. Rosenson, MD, FACC, FACP, FAHA, FNLA: Advisory Board: Abbott, Amgen, AstraZeneca, LipoScience Inc., Sanofi-Aventis; Stock Holdings: LipoScience Inc.•Michael Miller, MD, FACC, FAHA: Consultant: Amarin, Abbott, Roche; Research: Abbott, Merck, Roche; Speaker: Merck•Eliot A. Brinton, MD, FAHA, FNLA: Consultant: Abbott, Amarin, Daiichi-Sankyo, Essentialis, GlaxoSmithKline, Merck, Roche; Speaker: Abbott, Amarin, Daiichi-Sankyo, GlaxoSmithKline, Merck; Researcher: Abbott, Amarin, Merck; Scientific Advisory Board: Atherotech

Non-faculty DisclosuresNon-faculty Disclosures

Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:

•Barry Watkins, PhD; Bradley Pine; Blair St. Amand; Jay Katz; Dana Simpler, MD:Nothing to Disclose

Educational ObjectivesEducational Objectives

At the conclusion of this activity, participants should be able to demonstrate the ability to:

•Examine the extent of residual CVD risk that continues to burden dyslipidemic ACS patients despite intensive statin treatment

•Compare the relative effectiveness of existing treatments to raise HDL and reduce CVD risk

•Explain the rationale for developing CETP modulators and inhibitors to increase HDL and reduce CVD risk

•Discuss how the modulation of complex cholesterol metabolism could have an impact on atherogenesis and improve clinical outcomes

Key Learning MessagesKey Learning Messages

• Residual CVD Risk in High-Risk Dyslipidemic Patients– Lowering LDL-C reduces CVD risk in ACS patients and in general, but– There is residual CVD risk even with LDL-C controlled on statins

• Relative Prognostic Value of LDL-C and HDL-C for CVD Event Risk– LDL-C is usually not elevated at time of ACS (average LDL-C ~100 mg/dL)– HDL-C is usually low at time of ACS (average < 40 mg/dL) – Low HDL-C is a strong CVD risk factor independent of LDL-C and non-HDL-C

• Growing Appreciation of the Complexities of HDL Metabolism– HDL particles are heterogeneous in composition and functionality– Cholesterol efflux by HDL may reflect its antiatherogenic effect

• Rationale for Targeting HDL-C in High-Risk Patients– The many potential antiatherogenic effects of HDL may be clinically important– Raising low HDL-C may increase HDL benefits and may be a potential target of therapy

• Current and Emerging Therapeutic Options to Increase HDL Levels– Niacin increases HDL-C and may reduce CVD risk, but data are inconclusive– CETP inhibitors increase HDL-C and might reduce CVD risk

Attributable Declines in CHD Deaths Between 1980 and 2000 Attributable Declines in CHD Deaths Between 1980 and 2000

47%

Net 44%

Therapies Lifestyle/RFs

Attri

buta

ble

redu

ctio

n in

CHD

dea

ths

(%)

Ford ES et al. N Engl J Med. 2007;356:2389-2398.

Unexplained

↑TG,↓HDL-CTarget Population

↑TG,↓HDL-CTarget Population

Lowering LDL-C Reduces CVD Risk in Patients with CAD

Rationale for therapeutic lowering of Apo B lipoproteins: decrease the probability of inflammatory response to retention

High Plasma Apo B Lipoprotein Levels Promote AtherogenesisHigh Plasma Apo B Lipoprotein Levels Promote Atherogenesis

BloodApo B lipoproteinparticles

ModificationMacrophage

Monocytes bind toadhesion molecules

Smooth muscle

Foam cell

Inflammatory response

The Apo B-containing (non-HDL) Lipoprotein Family: All AtherogenicThe Apo B-containing (non-HDL) Lipoprotein Family: All Atherogenic

*ApoB is a component of all lipoprotein particles currently considered atherogenic2

Apo = apolipoprotein; IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein; Lp(a) = lipoprotein (a)1. Olofsson SO et al. Vasc Health Risk Manag. 2007;3:491-502. 2. Grundy SM. Circulation. 2002;106:2526-2529.3. Kunitake ST et al. J Lipid Res. 1992;33:1807-1816.

Images available at: http://www.mc.vanderbilt.edu/lens/article/?id=186&pg=999. Accessed January 2010. Adapted with permission.

*ApoB is a component of all lipoprotein particles currently considered atherogenic2

Apo = apolipoprotein; IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein; Lp(a) = lipoprotein (a)1. Olofsson SO et al. Vasc Health Risk Manag. 2007;3:491-502. 2. Grundy SM. Circulation. 2002;106:2526-2529.3. Kunitake ST et al. J Lipid Res. 1992;33:1807-1816.

Images available at: http://www.mc.vanderbilt.edu/lens/article/?id=186&pg=999. Accessed January 2010. Adapted with permission.

ApoB*ApoB*

LDL

ApoB-containing lipoproteins1

– LDL—most common/most important

– IDL– VLDL /VLDL remnants– Chylomicron remnants– Lp(a)

CHD Events Are Reduced Proportional to LDL-C Lowering w/ Statins: ACS &Other 2o Prevention Trials

Updated from O’Keefe J et al. J Am Coll Cardiol. 2004;43:2142-46.

y = 0.1629x · 4.6776R² = 0.9029P <0.0001

LDL Cholesterol (mg/dL)

CH

D E

vent

s (%

)

PROVE-IT-PR

PROVE-IT-AT CARE-S

LIPID-S

HPS-S4S-S

HPS-P

CARE-P

LIPID-P

4S-P

0

5

10

15

20

25

30

30 50 70 90 110 130 150 170 190 210

TNT 80TNT 10A2Z 80

A2Z 20

IDEAL S20/40IDEAL A80

There is Much Residual CVD Risk with Statins, Even with Intensive Therapy

Residual CVD Risk in Statin vs Placebo TrialsResidual CVD Risk in Statin vs Placebo Trials

4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333:1301-1307.6 Downs JR et al. JAMA. 1998;279:1615-1622.

14S Group. Lancet. 1994;344:1383-1389.2LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 3Sacks FM et al. N Engl J Med. 1996;335:1001-1009.

LDLN 4444 4159 20 536 6595 66059014

-35% -28% -29% -26% -25%-25%Secondary High Risk Primary

Patie

nts

Expe

rienc

ing

Maj

or C

HD E

vent

s, %

4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/TexCAPS6

PlaceboStatin

19.4

12.310.2 8.7

5.5 6.8

28.0

15.913.2

11.8

7.910.9

Many CHD Events Still Occur in Statin-Treated Patients

25-40% CVD Reduction Leaves High Residual RiskP = 0.003

P <0.001P = 0.003

P = 0.0001P <0.001

P <0.001

Residual CVD Risk with Intensive Statin Therapy Less, but Still Unacceptably High

Patie

nts

Expe

rienc

ing

Maj

or C

VD E

vent

s, %

PROVE IT-TIMI 222 IDEAL3 TNT4

nLDL-C* mg/dL

1Superko HR. Br J Cardiol. 2006;13:131-136. 2Cannon CP et al. N Engl J Med. 2004;350:1495-1504.3Pedersen TR et al. JAMA. 2005;294:2437-2445. 4LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

4162 8888 10,00195

*Mean or median LDL-C after treatment

62 104 81 101 77

Statistically significant, but clinically inadequate CVD reduction1

Standard statin therapyIntensive high-dose statin therapy

Placebo 251 / 8901

Rosuvastatin 20 mg/d 142 / 8901

HR 0.56, 95% CI 0.46-0.69P < 0.00001

Number Needed to Treat (NNT5) = 25

- 44 %

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulat

ive In

ciden

ce

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157

8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

High Residual CVD Risk Remains Even with High-dose Rosuvastatin (JUPITER)

Primary trial endpoint: MI, Stroke, UA/ Revascularization, CV Death

Ridker PM. N Engl J Med. 2008;359:2195-2207.

A Case of Residual CVD Risk on Statin TherapyA Case of Residual CVD Risk on Statin Therapy

• Patient Profile: 57-year-old white male (w/ stressful job)– Known CAD (preclinical)– BMI 27 kg/m2

– LDL-C 67 mg/dL– Triglycerides 300 mg/dL – HDL-C 32 mg/dL– Treadmill ECG: achieved target heart rate w/o angina/ischemia

• Medications– Statin, blood pressure medication, aspirin

• Does this patient require additional treatment? If so, what?

A Case of Residual CVD RiskA Case of Residual CVD Risk

• July 2010—clinic visit– Known CAD (preclinical)– BMI 27 kg/m2

– Statin compliant– LDL-C 67 mg/dL; Triglycerides 300 mg/dL; HDL-C 32 mg/dL– Treadmill ECG: achieved target heart rate w/o angina/ ischemia

• September 2010—sudden death– AMI and collapse at work– Attempts to resuscitate fail

• How could this have been avoided?

Annual CHD Event Rate Based on the Framingham Risk ScoreAnnual CHD Event Rate Based on the Framingham Risk Score

Braunwald E. J Am Coll Cardiol. 2006;47(8 Suppl):C101-C103.Wood D et al. Eur Heart J. 1998;19:A12-A19.

FRAMINGHAM RISK FACTORS

CaseAge: 57 yearsGender: maleTotal cholesterol: 150mg/dLHDL cholesterol: 32 mg/dLSmoker: noSystolic BP: 120 mm HgOn HBP meds: yes

TEN YEAR RISK SCORE: 10%

CAD Hospitalization and Temporal TrendsCAD Hospitalization and Temporal TrendsIn Lipid Levels from 2000-2006 (Mean)In Lipid Levels from 2000-2006 (Mean)CAD Hospitalization and Temporal TrendsCAD Hospitalization and Temporal TrendsIn Lipid Levels from 2000-2006 (Mean)In Lipid Levels from 2000-2006 (Mean)

108

43

150

108

43

172

107

41

168

107

41

162

105

40

162

103

38

161

103

38

167

0

20

40

60

80

100

120

140

160

180

LDL → LDL-C HDL → HDL-C TG → Triglycerides

Lipi

d Le

vel (

mg/

dL)

2000 2001 2002 2003 2004 2005 2006

Sachdeva A et al. Am Heart J. 2009;157:111-117.e2.

LDL-C HDL-C Triglycerides

Lifetime Risk for CVD Increases With Greater Risk Factor BurdenLifetime Risk for CVD Increases With Greater Risk Factor Burden

Life

time

Risk

for C

VD, %

All Optimal ≥1 Not Optimal ≥1 Elevated 1 Major ≥2 Major

Women

Men

8 5

27

36 3946

39

50 50

69

Risk Factor Burden at Age 50 (Estimated Risk by Age 95)

0

10

20

30

40

50

60

70

80

Lifetime burden stratified for risk factor burden years among Framingham Heart Study participants free of CVD at 50 years.Optimal risk factors defined as total cholesterol <180 mg/dL, BP <120/<80 mmHg, nonsmoker, and nondiabetic. Nonoptimal risk factors are defined as total cholesterol 180–199 mg/dL, systolic BP 120–139 mmHg, diastolic BP 80–89 mmHg, nonsmoker, and nondiabetic. Elevated risk factors are defined as total cholesterol 200–239 mg/dL, systolic BP 140–159 mmHg, diastolic BP 90–99 mmHg, nonsmoker, and nondiabetic. Major risk factors are defined as total cholesterol ≥240 mg/dL, systolic BP ≥160 mmHg, diastolic BP ≥100 mmHg, smoker, and diabetic. CVD = cardiovascular disease; BP = blood pressure.

Lloyd-Jones DM et al. Circulation. 2006;113:791-798.

≥2 major risk factors

1 major risk factor

≥ 1 elevated risk factor

≥1 risk factor not optimal

all risk factors optimal

Data were derived from 17 studies in a pooled cohort

Berry JD et al. N Engl J Med. 2012;366:321-329.

0 60 70 80 90

010

2030

40

Life

time

Ris

k (%

)

Attained Age (yr)

Lifetime Risk of Death from CVDAmong Black Men and White Men at 55 Years of Age

55 65 75 85

Lowering LDL-C Alone only Moderately Reduces CHD RiskLowering LDL-C Alone only Moderately Reduces CHD Risk

• Statins decrease CVD 25%-45% but leave 55-75% events not prevented1,2

• Despite on-Rx LDL-C <70-80 mg/dL, many ACS and other 2o prevention patients still have CVD events3,4,5 and these are related to low HDL-C5

• There is a great need for further improvement in cardiovascular risk reduction beyond statins6

CHD = coronary heart disease

Low HDL-C is an Independent CVD Risk Factor

CHD Risk According to HDL-C LevelsThe Framingham Heart StudyCHD Risk According to HDL-C LevelsThe Framingham Heart Study

Kannel WB. Am J Cardiol 1983;52:9B-12B.Copyright ©1983, with permission from Excerpta Medica Inc.

4.0

3.0

2.0

1.0

25 45 65HDL-C (mg/dL)

CH

D ri

sk ra

tio

2.0

1.0

0

4.0

Framingham Heart StudyLow HDL-C Predicts CHD Independent of LDL-CFramingham Heart StudyLow HDL-C Predicts CHD Independent of LDL-C

Castelli W. Can J Cardiol. 1988;4(suppl A):5a-10a.

HDL-Cmg/dL

CAD Risk After 4 Years*

LDL-C, mg/dL

8565

4525

100 160 2200

1

2

3

*Men aged 50-70 years

HDL-C is inversely correlated with CAD risk

Correlation is independent of LDL-C

HDL-C Quintiles,a mg/dL

5-Ye

ar R

isk o

f Maj

or C

VD E

vent

s, %

Low HDL-C Predicts Residual CVD Risk After Optimal Statin Rx: TNT Study

LDL-C ≤70 mg/dL on Statina,b

(Treating to New Targets (TNT) Study)

aOn-treatment level (3 months statin therapy); n = 2661bMean LDL-C, 58 mg/dL; mean TG, 126 mg/dL *P=.03 for differences among quintiles of HDL-C Barter P et al. New Engl J Med. 2007;357:1301-1310.

Q1<37

Q237 to <42

Q342 to <47

Q5≥55

Q447 to <55

Hazard RatioVersus Q1* 0.85 0.57 0.55 0.61

Case: HDL-C 32; LDL-C 67 on statin

Early and Late Mortality Post-DES Low HDL-C vs High HDL-C at BaselineEarly and Late Mortality Post-DES Low HDL-C vs High HDL-C at Baseline

Wolfram RM et al. Am J Cardiol. 2006;98:711-717.

High HDL-C

Low HDL-C

HDL Consists of Heterogeneous Particles, but Their Clinical Relevance

Remains to Be Established

Separation of HDL by Physical PropertiesSeparation of HDL by Physical Properties

• Ultracentrifugation – density – Isopycnic – preparative– Density Gradient – Vertical automated profile (VAP)

• Gradient gel electrophoresis (GGE) – size • Rocket immunoelectrophoresis – apolipoprotein content• Nuclear magnetic resonance (NMR) – terminal methyl• 2-D gel electrophoresis – size and charge (shape)• Ion mobility – charge (shape) and mass

Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ.Clin Chem. 2011;57(3):392-410.

HDLHDL2a2aHDLHDL2b2b HDLHDL3c3cHDLHDL3b3bHDLHDL3a3a

HDL HDL ParticleParticle SizeSize/Electrophoretic Mobility/Electrophoretic Mobility

Apolipoprotein ContentApolipoprotein Content Particle ShapeParticle Shape

DiscoidalDiscoidal

SphericalSphericalA-I HDLA-I HDL A-I/A-II HDLA-I/A-II HDL

Lipid-poor apoA-ILipid-poor apoA-I

HDL Subpopulations HDL Subpopulations

+other apos: A-IV, C, D, E, etc.+other apos: A-IV, C, D, E, etc.+non-apo proteins: inflam, thromb, etc.+non-apo proteins: inflam, thromb, etc.

--------------------------Alpha-migrating------------------------- --Pre-beta-migrating----Pre-beta-migrating--

Globular Discoidal

Globular

Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39-47.

Potential Antiatherogenic Actions of HDLPotential Antiatherogenic Actions of HDL

MCP-1 = monocyte chemoattractant protein-1

Adapted from Barter PJ et al. Circ Res. 2004;95:764-772.

Monocyte

MacrophageFoam

cell

Vessel Lumen

Endothelium

IntimaCytokines

Adhesion molecule

Oxidized LDL

LDL

LDL

HDL inhibits expression of endothelial cell adhesion molecules and MCP-1

MCP-1

HDL inhibits oxidation of LDL-C

HDL promotes efflux of cholesterol from foam cells

Processes Promoting Efflux of Cholesterol from Cells to HDL ParticlesProcesses Promoting Efflux of Cholesterol from Cells to HDL Particles

Adapted from Barter P, Rye KA. High density lipoprotein cholesterol: the new target. A handbook for clinicians. 3rd ed. Birmingham, UK: Sherbourne Gibbs, 2007:31.

Rosen R et al. Circulation. 2012.

Extracellular space Cell membrane

FC

FC

FC

FC

ABCA1

Diffusion

SR-B1

Diffusion

SR-B1ABCG1

Diffusion

SR-B1ABCG1

Discoidal HDL

Small spherical HDL

Larger spherical HDL

LCAT

LCAT

Cholesterol deficient, phospholipid depleted apo A-1

Proposed Term Very Large HDL

(HDL-VL) Large HDL-V

(HDL-L) Medium HDL

(HDL-M) Small HDL (HDL-S)

Very Small HDL (VS-HDL)

Density range, g/mL 1.063-1.087 1.088-1.110 1.110-1.129 1.129-1.154 1.154-1.21

Size range, nm 12.9-9.7 9.7-8.8 8.8-8.2 8.2-7.8 7.8-7.2

Density gradient ultracentrifugation

HDL2b HDL2a HDL3a HDL3b HDL3c

Density range, g/mL 1.063-1.087 1.088-1.110 1.110-1.129 1.129-1.154 1.154-1.170

Gradient gel electrophoresis

HDL2b HDL2a HDL3a HDL3b HDL3c

Size range, nm 12.9-9.7 9.7-8.8 8.8-8.2 8.2-7.8 7.8-7.2

2D gel electrophoresis Alpha-1 Alpha-2 Alpha-3 Alpha-4 Preβ-1 HDL

Size range, nm 11.2-10.8 9.4-9.0 8.5-7.5 7.5-7.0 6.0-5.0

NMR Large HDL-P Medium HDL-P Small HDL-P

Size range, nm 12.9-9.7 9.7-8.8 8.8-8.2 8.2-7.8 7.8-7.2

Ion mobility HDL2b HDL2a + 3

Size range, nm 14.5-10.5 10.5-7.65

Classification of HDL by Physical Properties

Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ.Clin Chem. 2011;57(3):392-410.

Functional and Compositional Assessment of HDLFunctional and Compositional Assessment of HDL

• Cholesterol efflux

• Antioxidant activity

• Anti-inflammatory activity

• Proteomics/lipidomics

Note: these are research tools w/o known clinical relevance of application

Rosenson RS, Brewer HB Jr, Chapman MJ, Fazio S, Hussain MM, Kontush A, Krauss RM, Otvos JD, Remaley AT, Schaefer EJ.Clin Chem. 2011;57(3):392-410.

HDL-C Risk Factor vs Risk Marker?HDL-C Risk Factor vs Risk Marker?

• Low HDL-C predicts high CVD Risk• High HDL-C predicts anti-atherogenic effects:

– Anti-inflammatory– Antioxidant– Antithrombotic– Pro-endothelial

• But clinical trials have not yet proven that:– HDL is a causal factor vs biomarker of risk, or– Raising HDL-C reduces CVD risk

Should High-density Lipoprotein Be a Target of Therapy ?Should High-density Lipoprotein Be a Target of Therapy ?

• ATP III Guidelines on HDL-C: “Current documentation of risk reduction through controlled clinical trials is not sufficient to warrant setting a specific goal value for raising HDL-C” (Grundy SM et al. Circulation. 2004;110:227-239)

• Failure of ACCORD, FIELD, AIM-HIGH and the experience with torcetrapib have increased doubts as to the value of raising HDL-C

• Recent clinical trial data from next generation investigational CETP inhibitors has refueled hope that this approach may increase HDL-C and improve clinical outcomes

• Smoking Cessation− HDL-C levels are 7-20% lower in smokers, but return to normal 1-2 months

after smoking cessation• Whole Food Plant Based Diet• Weight Reduction

− For every 3 kg (7 lb) of weight loss, HDL-C levels increase about 1 mg/dL (~2-4% increase)

• Exercise− Aerobic exercise (40 min, 3-4 times weekly) increases HDL-C by about 2.5

mg/dL (~5-10% increase)

Rössner S et al. Atherosclerosis. 1987;64:125-130.Wood PD et al. N Engl J Med. 1988;319:1173-1179.Ornish D et al. JAMA. 1998;280:2001-2007.

Lifestyle Modifications to Raise HDL-C LevelsLifestyle Modifications to Raise HDL-C Levels

Cullen P et al. Eur Heart J. 1998;19:1632-1641.Kokkinos PF et al. Arch Intern Med. 1995;155:415-420.Kodama S et al. Arch Intern Med. 2007;167:999-1008.

Reducing CAD Risk in Patients with DyslipidemiaReducing CAD Risk in Patients with DyslipidemiaReducing CAD Risk in Patients with DyslipidemiaReducing CAD Risk in Patients with Dyslipidemia

Established

LDL-C

HDL-C Triglycerides

Lp(a)

Oxidized LDL

Small dense LDL

Homocysteine

CRP

Coagulability

Reasonable EvidenceReasonable Evidence

Not EstablishedNot Established

Available Agents for HDL-C RaisingAvailable Agents for HDL-C RaisingAgent HDL-C ↑ Primary UseNicotinic acid 15-35% HDL ↑Fibrates 5-20% TG ↓Statins 5-15% LDL ↓Prescription Om-3* 2-10% TG ↓Bile-acid resins* 2-5% LDL ↓Ezetimibe* 1-3% LDL ↓Pioglitazone* 5-20% Glucose ↓Estrogens* 10-25% Hot flashes-blockers* 10-20% BPHAlcohol* 5-15% Social, etc.

*Lacking FDA-approved indication for HDL-raising.Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41:151-174.Insull W et al. Mayo Clin Proc. 2001;76:971-982.McKenney JM et al. Pharmacother. 2007;27:715-728.

Risk Reduction for CHD EventsAs a Function of Changes in TC, LDL-C, and HDL-CRisk Reduction for CHD EventsAs a Function of Changes in TC, LDL-C, and HDL-C

*4S, CARE, LIPID, WOSCOPS**HELSINKI, VA-HIT,AFCAPS/TexCAPS

PERCENT CHD EVENTCHANGE RATE

Niacin Increases HDL-C, but May Not Consistently Reduce CVD Risk

CVSurgery

Niacin Reduces CVD EventsCoronary Drug ProjectNiacin Reduces CVD EventsCoronary Drug Project

Coronary Drug Project. JAMA. 1975;231:360-381. Canner PL et al. J Am Coll Cardiol. 1986;8:1245-1255.

• Subjects: men with prior MI

• Treatment arms, 5 lipid meds:

– IR Niacin, 1 g TID (n=1119) estrogen (2 arms), dextrothyroxine, clofibrate

– Niacin lipid effects: TC 10%, TG 27% (HDL-C not meas.)

• Results (6 yrs, end-study): benefit only seen in Niacin arm ( MI 27%, no 1o endpoint=total mortality)

• Post-study f/u 15 yrs: 4% absolute total mortality (NNT = 25)

Event Rate (%)

Nonfatal MI/CHD Death

Nonfatal MI

Stroke/TIA

Placebo

Niacin

–14

–27–26

–47

0

5

10

15

20

25

30

35

Niacin Reduces CVDPre-AIM-HIGH TrialsNiacin Reduces CVDPre-AIM-HIGH Trials

Many of these trials were tests of drug combinations that included niacin.Bruckert E et al. Atherosclerosis. 2010;210:353-361.

stat sig 27%↓

AIM-HIGH—Design AIM-HIGH—Design

• Purpose: “[A] rigorous test of the HDL hypothesis…”• Subjects: N=3414 men/women (85%/15%) w/ prior CVD event

and HDL-C 35 (<42/53) LDL-C 74 (algorithm), TG 163 (100-400) [median (range)]

• Randomized Therapy– Extended-release niacin (1500-2000 mg hs) vs– “Placebo” (immediate-release niacin 100-150 mg hs)

• Open-label titration/addition (keep LDL-C in 40-80 mg/dL)– Simvastatin 5-80 mg/d– Ezetimibe 10 mg/d + extended release niacin (1500-2000 mg)

AIM-HIGH Investigators. N Engl J Med. 2001;365:2255-267.AIM-HIGH Investigators. Am Heart J. 2011;161:471-477.e2.

Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.

AIM-HIGH—ResultsHDL-C at Baseline and Follow-up

1o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization

Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.

AIM-HIGH—ResultsPrimary Outcome

AIM-HIGH Early TerminationAIM-HIGH Early Termination• Lipids

– Baseline: LDL-C 71 mg/dL w/ prior stain Rx (94% of subjects)– On Rx: HDL-C ↑ 25% ERN vs ↑ 10% “placebo” (<2/3 of projected)

• Data, Safety and Monitoring Board chose early termination– Due to futility (likely lack of efficacy) - 1° Endpoint HR 1.05– Early concern about possible increased stroke rate signal

• Potential explanations for lack of observed efficacy:– “Placebo” arm received IR niacin, ↑ statin dose & ↑ ezetimibe

(poor test of HDL hypothesis w/ just 15% net ↑ HDL-C)– Early study termination (VA HIT also negative at 3 y)– Sl lower than expected event rate (but still >5%/yr)– High prior statin use (94%, 40%>5y), prior niacin use (20%)

Press conference transcript; May 26, 2011. Available at: www.nhlbi.nih.gov/new/remark/aim-high-transcript.htm. Brinton EA. J Clin Lipi. 2011.Rosenson RS. Curr Athero Rep. 2012 (in press).

CV

D E

ven

ts p

er

Stu

dy

AIM-HIGH is Small Relative to Earlier and Later Niacin Clinical TrialsAIM-HIGH is Small Relative to Earlier and Later Niacin Clinical Trials

*At publication 11/15/11. **Estimated. Results due in ~1 year. Bruckert E et al. Athero. 2010;210:353-361.

3515

556*

~2300**

~1/7

~4 x

Study Treatmentn/N

Controln/N

Peto OR95% Cl

Peto OR 95% Cl

ARBITER-6-HALTS 2/187 9/176 0.25 (0.08, 0.84)

Guyton JR et al 1/676 1/272 0.35 (0.02, 7.56)

AFREGS 0/71 1/72 0.14 (0.00, 6.92)

ARBITER-2 2/87 2/80 0.92 (0.13, 6.65)

HATS 1/38 5/38 0.24 (0.05, 1.26)

UCSF_SCOR 0/48 1/49 0.14 (0.00, 6.96)

STOCKHOLM 72/279 100/276 0.61 (0.43, 0.88)

CLAS 1/94 5/94 0.25 (0.05, 1.29)

CDP 287/1119 839/2789 0.81 (0.69, 0.94)

Total Test for heterogeneity: P = 0.24, I2 = 23.0% Test for overall effect: P < 0.0001

0.75 (0.65, 0.86)

Subtotal excluding CDP 0.53 (0.38, 0.73)

0.1 0.2 0.5 1 2 5 10Log scale

Meta-Analysis: Effects of Nicotinic AcidMajor Coronary EventsMeta-Analysis: Effects of Nicotinic AcidMajor Coronary Events

Many of these trials were tests of drug combinations that included niacinBruckert E et al. Atherosclerosis. 2010;210:353-361.

Study N TreatmentMean (SD)

N ControlMean SD

WMD (fixed)95% Cl

WMD (fixed)95% Cl

ARBITER-6-HALTS 97 -12 (36) 111 -1 (31) -12 (-21, -2)

Thoenes M et al 30 -5 (11) 15 9 (12) -14 (-21, -7)

ARBITER-2 78 14 (104) 71 44 (100) -30 (-63, -3)

CLAS 39 -12 (20) 39 12 (20) -25 (-34, -16)

Total Test for heterogeneity: P = 0.13, I2 = 47.4% Test for overall effect: P < 0.0001

-17 (-22, -12)

Meta-Analysis: Effects of Nicotinic Acid Carotid Intima Media ThicknessMeta-Analysis: Effects of Nicotinic Acid Carotid Intima Media Thickness

-100 -50 0 50 100Annual change, μm/y

E. Bruckert et al, Atherosclerosis 210 (2010) 353-361

CETP Inhibitors/Modulators Increase HDL-C and May Reduce

Atherosclerosis

Role of CETP in AtherosclerosisRole of CETP in Atherosclerosis

• Human CETP deficiency– ↑ in HDL-C (codominant) – ↓CVD

• Reducing CETP activity →↓atherosclerosis in animal models

Barter PJ et al. Arterioscler Thromb Vasc Biol. 2003;23:160-167.Contacos C et al. Atherosclerosis. 1998;141:87-98. Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28: 148-154.

LIVER PERIPHERAL TISSUE

CE

TG

Bile

Foamcells

RCT HDL

ABC-A1

VLDL LDL

PLASMA

LDL-R

ABC-G1

Free cholesterol

CETP

Athero-sclerosisLDL

Development of CETP Inhibitors/Modulators

CETP Inhibitors and ModulatorsCETP Inhibitors and Modulators

CETP

Evacetrapib

Lipid Effects of CETP Inhibitors/Modulators% Change from BaselineLipid Effects of CETP Inhibitors/Modulators% Change from Baseline

CETP Agent Dose (Mg/day) HDL-C (%) LDL-C (%) TG (%)

Torcetrapib 60 61 -24 -9

Anacetrapib 100 138 -40 -7

Evacetrapib 500 129 -36 -11

Dalcetrapib 600 31 -2 -3

Adapted from Cannon C et al. JAMA. 2011;306:2153-2155. Nicholls SJ et al. JAMA. 2011;306:2099-2109.

Torcetrapib“Beneficial” Effects on LipoproteinsTorcetrapib“Beneficial” Effects on Lipoproteins

Is the toxicity of torcetrapib related to the mechanism or the molecule?

Placebo 60 mg 90 mg 120 mg

Barter PJ et al. N Engl J Med. 2007;357:2109-2122.

HDL-C

LDL-C

+42%+49%

+55%

-20%-18%

-1%

+1% +1%

Is the toxicity of torcetrapib related to the mechanism or the molecule?

Atorvastatin only

Torcetrapib plus atorvastatin

0 90 180 270 360 450 540 630 720 810

Days After Randomization

Patie

nts

With

out E

vent

(%)

100

98

96

94

92

90

0

Barter PJ et al. N Engl J Med. 2007;357:2109-2122.

Torcetrapib: BUT Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality Torcetrapib: BUT Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality

HR = 1.25P = 0.0001

Torcetrapib Caused Off-target HyperaldosteronismTorcetrapib Caused Off-target Hyperaldosteronism

• Torcetrapib arm of ILLUMINATE trial showed significant:1

– ↑ Systolic Blood Pressure: Mean ↑5.4 mmHg >15 mmHg ↑ SBP: 19.5% torcetrapib arm (vs 9.4% placebo arm, p<0.001)

– ↓ serum potassium– ↑ serum bicarbonate– ↑ serum sodium– ↑ serum aldosterone

• Inverse relationship of CVD and on-Rx-HDL-C preserved• Conclusion: ↑ CVD in ILLUMINATE likely due to off-target actions of

torcetrapib, not related to CETP inhibition1,2

1. Barter PJ et al. N Engl J Med. 2007;357:2109-2122.2. Rosenson RS. Curr Athero Rep. 2008;10:227-229.

Analysis of the Off-target Characteristics of Investigational CETP Inhibitors/ModulatorsAnalysis of the Off-target Characteristics of Investigational CETP Inhibitors/Modulators

Characteristic Torcetrapib Anacetrapib Dalcetrapib Evacetrapib

Clinical evidence of increased BP Yes1 No2 No3 No7

Preclinical evidence of increased aldosterone production* Yes3 No4 No3 No8

Preclinical evidence of aldosterone synthase (CYP11B2) mRNA induction*

Yes3 ? No3 ?

Preclinical evidence of RAAS-associated gene induction* Yes5 ? No5 ?

L-type Ca2+ channel activation* Yes6 ? No6 ?

1. Barter et al. N Engl J Med. 2007;357:2109-2122. 2. Masson D. Curr Opin Invest Drugs. 2009;10:980-987. 3. Stein et al. Am J Cardiol. 2009;104:82-91. 4. Forrest et al. Br J Pharmacol. 2008;154:1465-1473. 5. Stroes et al. Br J Pharmacol. 2009;158:1763-1770. 6. Clerc et al. J Hypertens. 2010: in press. 7. Nicholls et al. JAMA 2011;306:2099-2109 8. Cao et al. J Lipid Research. 2011;52:2169-2176

Anacetrapib Effects on LDL-C and HDL-CAnacetrapib Effects on LDL-C and HDL-C

HDL-C

Baseline 6 12 18 24 30 46 62 76

HD

L-C

(mg/

dL) (

SE)

0

20

40

60

80

100

120

AnacetrapibPlacebo

Anacetrapib n =Anacetrapib n = 776 757 718 687 647 607 572 543

Placebo n =Placebo n = 766 761 741 744 736 711 691 666

LDL-C

Study WeekBaseline 6 12 18 24 30 46 62 76

LDL-

C (m

g/dL

) (SE

)

0

20

40

60

80

100

AnacetrapibPlacebo

Anacetrapib n = 804 771 716 687 646 604 568 540

Placebo n = 803 759 741 743 735 711 691 666

-39.8% (P<0.001) +138.1% (P<0.001)

Cannon CP et al. N Engl J Med. 2010;363:2406-2415.

Study Week

Dalcetrapib Phase IIb TrialHDL-C Increase at Week 12Dalcetrapib Phase IIb TrialHDL-C Increase at Week 12

placebon = 73

dalcetrapib300 mgn = 75

NOTE: Dalcetrapib 600 mg is the dose used in phase III

Stein EA. Am J Cardiol. 2009;104:82-91.

*

**P <0.0001 vs placebo

*

dalcetrapib600 mgn = 67

dalcetrapib900 mgn = 72

Cha

nge

From

Bas

elin

e (%

)C

hang

e Fr

om B

asel

ine

(%)

Dalcetrapib (JTT-705) Attenuates Atherosclerosis in RabbitsDalcetrapib (JTT-705) Attenuates Atherosclerosis in Rabbits

Okamoto H et al. Nature. 2000;406:203-207.

Dalcetrapib and Torcetrapib Appear to Differ in Mechanism of CETP InhibitionDalcetrapib and Torcetrapib Appear to Differ in Mechanism of CETP Inhibition

1Okamoto H et al. Nature. 2000;406:203-207. 2Niesor EJ et al. Atherosclerosis. 2008;199:231. 3Clark RW et al. J Lipid Res. 2006;47:537-552.

NB: The clinical relevance of these differences is unknown; these compounds have not been studied in head-to-head clinical trials.

dalHDL

tor or ana

CETP

HDL

• Dalcetrapib binds to CETP, inducing a conformational change to CETP that hinders association to HDL1

• Dalcetrapib binds to CETP only2

• Torcetrapib binding to CETP is an irreversible high affinity complex of CETP inhibitor, HDL, and CETP2,3

“The dal-OUTCOMES trial evaluated the efficacy and safety profile of dalcetrapib when added to existing standard of care in patients with stable coronary heart disease following an acute coronary syndrome.

Following the results of the second interim analysis of the dalcetrapib dal-OUTCOMES Phase III trial the Independent Data and Safety Monitoring Committee (DSMC) has recommended stopping the trial due to a lack of clinically meaningful efficacy. No safety signals relating to the dal-OUTCOMES trial were reported from the DSMC.

As a result, Roche has decided to terminate the dal-OUTCOMES trial, as well as all other on-going studies in the dal-HEART program, including dal-PLAQUE 2 and dal-OUTCOMES 2. Additional information will be provided in due course as data become available.

Excerpt from letter to dal-OUTCOMES Investigators from Roche.

Termination of Dalcetrapib Clinical Trial 7/7/2012Termination of Dalcetrapib Clinical Trial 7/7/2012

”

ConclusionsConclusions

• Residual CV risk remains problematic despite statin-mediated Residual CV risk remains problematic despite statin-mediated LDL-C reduction LDL-C reduction

• Low HDL-C is an independent risk factor for CHD Low HDL-C is an independent risk factor for CHD • Most clinical trial and observational data suggest that raising Most clinical trial and observational data suggest that raising

HDL-C may reduce CVDHDL-C may reduce CVD• HDL particles are very heterogeneous in composition and HDL particles are very heterogeneous in composition and

function, not all HDL may be anti-atherogenicfunction, not all HDL may be anti-atherogenic• Many new HDL-C raising treatments are in developmentMany new HDL-C raising treatments are in development• CETP inhibitors greatly raise HDL-C levels, but their effect on CETP inhibitors greatly raise HDL-C levels, but their effect on

HDL function and clinical outcomes remains in questionHDL function and clinical outcomes remains in question

Revisiting the HDL HypothesisWhere to Next?Revisiting the HDL HypothesisWhere to Next?

• Residual CVD risk exists despite intense statin monotherapy• Low HDL-C predicts high CVD risk; high HDL-C is protective • Existing HDL raising therapies have inconsistent effects• Investigational drugs to raise HDL-C and reduce CVD risk

– CETP inhibitors– PPAR agonists, APO A1 agonists, delipidating agents, etc.

• But clinical trials have not yet proven that:– HDL is a causal factor vs biomarker of risk– Raising HDL-C reduces CVD risk

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CVD RISK REDUCTION AND LIPID MANAGEMENTState of the Science in HDL Therapy