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LDL-C and CV Risk:What We Know and Don't Know

Joseph J. Saseen, PharmD, FCCP, BCPS, CLSAssociate ProfessorClinical Pharmacy and Family MedicineUniversity of Colorado Denver

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American Heart Association News 1/22/2008

Since 1999, death rates have dropped:– Coronary heart disease 25.8%

– Stroke 24.4%

Drops are ahead of goals set for the year 2010

“However, potential problems loom for the future, as all of the major risk factors for these leading causes of death are still too high and several are actually on the rise.”

http://www.americanheart.org/

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NHANES:Serum Lipids and Lipoproteins in Adults

215

49.7

138

114

204

50.7

129118

203

51.3

123 123

0

25

50

75

100

125

150

175

200

225

TotalCholesterol

HDL-Cholesterol

LDL-Cholesterol

Triglycerides

Mea

n V

alu

e (m

g/d

L)

1976-1980

1988-1994

1999-2002

Carroll MD et al. JAMA. 2005;294:1773-1781.

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LDL-C and CV Risk

Grundy SM et al. Circulation. 2004; 110:227-239.

30 mg/dL

30 mg/dL

30 mg/dL

30 mg/dL

30%

30%

30%

30%

1.0

1.3

1.7

2.2

2.9

3.7

40 70 100 130 160 190

LDL-Cholesterol (mg/dL)

Relative Risk for

Coronary Heart

Disease (log scale)

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Cholesterol Treatment Trialists’ Collaborators

Meta-analysis,14 randomized controlled trials (n=90,056)

Major Vascular Events (per 1 mmol/L LDL-C reduction)

21.2

8.5

26.9

10.6

0 5 10 15 20 25 30

Se

co

nd

ay

Pre

ve

nti

on

(Po

st-

MI)

Pri

ma

ryP

rev

en

tio

n(n

o C

HD

)

Event Rate (% )

Control

Statin

Both comparisons, P<0.001

Baigent C et al. Lancet. 2005;366:1267-1278.

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Lipid-Lowering Therapies

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. Zetia [package insert]. Merck/Schering-Plough Pharmaceuticals; 2005. Crestor [package insert]. Astra-Zeneca; 2005. Omacor [package insert]. Reliant Pharmaceuticals; 2005.

LDL-C HDL-C TG

Statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin)

18-63% 5-15% 7-30%

Bile Acid Sequestrants(colesevelam, cholestyramine, colestipol)

15-30% 3-5% 0 or

Nicotinic Acid 5-25% 15-35% 20-50%

Fibric Acid Derivatives(gemfibrozil, fenofibrate)

5-20 or 10-20% 20-50%

Cholesterol Absorption Inhibitor (ezetimibe)

18% 1% 7%

Omega-3 fatty acids(prescription strength only)

? 9% 45%

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HMG CoA Reductase Inhibitors (Statins)

X Competitive Inhibition

Cholesterol production

Expression of LDL

receptors

LDL, VLDL,

and IDL particles

LDL Lowering

HMG-CoA Reductase

Acetyl CoA

HMG-CoA

Mevalonate

Cholesterol production

Mechanism of Action – HMG CoA Reductase Inhibitors

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STELLAR TrialStatin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin

-29.7

-55.0

-45.8

-51.1

-45.8

-36.8

-28.3

-20.1

-52.4

-42.6

-35.0

-24.4

-47.8

-38.8

-60

-50

-40

-30

-20

-10

0

Pravastatin Simvastatin Atorvastatin Rosuvastatin

% L

DL

-C C

ha

ng

e f

rom

Ba

se

line

10mg

20mg

40mg

80mg

Jones PH et al. Am J Cardiol. 2003;92:152-160.

6-week, parallel groups, open-label study (n=2431)

Landmark Statin-based Outcome Trials

Jacobson TA et al. Arch Intern Med. 1998;158:1977-1989.; Heart Protection Study Collaborative. Lancet. 2002;360:7-22.; Shepherd J et al. Lancet. 2002; 360:1623-1630.; Sever PS et al. Lancet. 2003;361:1149-58.; Colhoun HM et al. Lancet. 2004;364:685-696.

Trial

LDL-C (mg/dL)Primary Endpoint/CV Event Rate (%)

Baseline Treatment Placebo StatinSecondary Prevention

4S 188 122 28.0 19.4

LIPID 150 112 15.7 12.3

CARE 139 98 13.2 10.2

Primary & Secondary Prevention

HPS 132 93 24.4 19.9

PROSPER 147 97 16.2 14.1

Primary Prevention

WOSCOPS 192 159 7.5 5.3

AFCAPS 150 115 5.5 3.5

ASCOT 133 90 3.0 1.9

CARDS 118 77 9.0 5.8

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Patients with CHD:Intensive Vs Moderate Statin Therapy

Meta-analysis of 4 major trials (PROVE-IT, A to Z, TNT, IDEAL); included 27,548 patients

Cannon CP et al. J Am Coll Cardiol. 2006;48:438-445.

P=0.054

P<0.0001P<0.0001

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Pleiotropic Effects of Statins?

Beneficial CV effects that are not related to LDL-C lowering– Anti-inflammatory effects

– Immunomodulatory effects

– Endothelial dysfunction improvement Increased nitric oxide bioavailability Decreased LDL-C oxidation

– Plaque stability

– Inhibiting the thrombogenic response

Liao JK, Laufs U. Ann Rev Pharmacol Toxicol. 2005;45:89-118. Tandon V. Indian J Pharmacol. 2005;37:77-85.

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HMG-CoA Reductase Expression

VLDL Production / Secretion

LDL Production

Bile Acid Sequestrants

Hepatic Bile Acid Pool

Hepatic Bile Acid Synthesis from Cholesterol

Intrahepatic Cholesterol Pool

LDL Receptors

LDL Clearance

Plasma LDL-C

Mechanism of Action – Bile Acid Sequestrants

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Bile Acid Sequestrants(colestipol, colesevelam, cholestyramine)

Provide modest reductions in LDL-CMay increase triglyceride values, especially

in patients with baseline hypertriglyceridemiaAvoid systemic toxicitiesSome can bind the absorption of other drugs

when administered simultaneouslyPrimary roles are in addition to statin-based

therapy or in statin-resistant patients

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Bile Acid Sequestrant Outcomes Data

LRC-Primary Prevention Trial (n=3086):– Cholestyramine reduced fatal CHD + non-fatal

MI 19% versus placebo over 7.4 yrs (7.0 vs 8.6%, P<0.05)

FATS Trial (n=146):– Intensive LDL-C lowering in CHD patients using

colestipol with lovastatin or niacin lowered CV event risk versus conventional therapy (HR=0.27, 0.10 to 0.77)

LRC-CPP Trial. JAMA. 1984;251:351-374. Brown G et al. N Engl J Med. 1990; 323:1289-1298.

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TG

HDL

Lipoprotein

lipase

VLDL

ApoB

LDL

ApoB

Fibric Acids

(Fibrates)

Liver

Mechanism of Action – Fibric Acid Derivatives

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Fibric Acid Derivatives(fenofibrate, gemfibrozil)

Provide significant reductions in triglycerides and can raise HDL-C

Have a limited ability to LDL-C and may paradoxically increase LDL-C

Primary roles are for hypertriglyceridemia or in addition to statin-based therapy for mixed dyslipidemia/non-HDL-C reduction

CV events reduced in certain primary (Helsinki Heart Study) and secondary prevention populations

Frick MH et al. N Engl J Med. 1987;317:1237-1245.

17Rubins HB et al. N Engl J Med. 1999;341;410-418.

Veterans Affairs HDL Intervention Trial (VA-HIT)

2531 men with CHD randomized to placebo or gemfibrozil 1200 mg/day x 5.1 yrs

Lipid differences placebo vs gemfibrozil:– HDL: 32 vs 34– LDL: 113 vs

113– TG: 166 vs

115

0

5

10

15

20

25

0 1 2 3 4 5 6Year

Cu

mu

lati

ve in

cid

enc

e (%

)

Death From CHD and Nonfatal MI

Placebo

Gemfibrozil

22%

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Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) 9795 patients with type 2

diabetes Randomized, double-blind

to placebo or fenofibrate 200mg daily x 5 yrs

Primary endpoint:– CHD death +nonfatal MI

Statin “drop-in” rate was high

Keech A et al. Lancet. 2005;366:1849–1861.

*Total CV events

P=0.16

P=0.35

0

5

10

15

PrimaryEndpoint

SecondaryEndpoint*

% P

atie

nts

PlaceboFenofibrate

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Niacin

Adipose tissueFA mobilization

TG Synthesis

FA synthesis/esterification

HDL-catabolismreceptor

HDL Apo A-Iuptake/removal

Large TG-rich VLDL

Apo B lipoproteins Apo B

degradation

VLDL, LDL-C Small dense LDL-C

Adapted from Kamanna VS, Kashyap ML. Curr Atheroscler Rep. 2000;2:36-46.

HDL

Mechanism of Action - Niacin

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Nicotinic Acid [a.k.a. Niacin]

Changes all lipid components favorably– Consistent LDL-C and triglyceride lowering

effects

– Raises HDL-C better than any other agent

Flushing is minimized with extended-release formulations and other modalities

Primary roles are for hypertriglyceridemia or in addition to statin-based therapy for mixed dyslipidemia/non-HDL-C reduction

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Nicotinic Acid Outcomes Data

HATS Trial (n=160)– Simvastatin + niacin reduced CV events versus placebo

over 3 yrs in patients (2.6 vs 23.7%, P<0.05)

Coronary Drug Project (n=1119)– After 6 yrs, IR niacin (up to 3 g/day) significantly reduced

MI compared with placebo in men with CHD

– 15 year follow-up data demonstrated reduced mortality

ARBITER-2 (n=167)– Significant reductions in carotid IMT with ER Niacin

(1 g/day) added to statin therapy versus placebo in patients with CHD

Brown BG et al. N Engl J Med. 2001;345:1583-1592.; JAMA .1975;231:360-381.; Canner PL et al. J Am Coll Cardiol. 1986;8:1245-1255.; Taylor AJ et al. Circulation. 2004;110:3512-3517.

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Mechanism of Action – Cholesterol Absorption Inhibitor

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Cholesterol Absorption Inhibitor(Ezetimibe)

Provides modest reduction in LDL-CPrimary role is in addition to statin-based

therapy or in statin-resistant patientsNo definitive outcomes data; however,

recent ENHANCE trial has had controversy– 720 patients with heterozygous familial

hypercholesterolemia randomized to ezetimibe/simvastatin 10/80 mg daily or simvastatin 80 mg daily for 2 yrs

www.theheart.org.

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ENHANCE: Results

Significant differences in LDL-C reduction:– Baseline LDL-C values: 319 and 318 mg/dL

– LDL- C reductions: 58 and 41% (P<0.01)

Primary Endpoint: Change in mean carotid IMT– Ezetimibe/Simvastatin 0.0111 mm

– Simvastatin 0.0058 mm (P=0.29)

Other Endpoints: Patients with CV Events– Ezetimibe/Simvastatin 12 of 357

– Simvastatin 9 of 363 (P=ns)

www.theheart.org.

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Trial on the Horizon

IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome

Randomized, double-blind trial comparing ezetimibe/simvastatin 10/40 mg daily vs simvastatin 40 mg daily

>10,000 patients who are stable after acute coronary syndrome

Primary endpoint: fatal and non-fatal CV event Results expected in 2011

www.clinicaltrials.gov.