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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.