LDL-C and CV Risk:
What We Know and Don't Know
Joseph J. Saseen, PharmD, FCCP, BCPS, CLS
Associate Professor
Clinical Pharmacy and Family Medicine
University 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/
2
NHANES:
Serum Lipids and Lipoproteins in Adults
Mean Value (mg/dL)
225
1976-1980
215
204
203
200
1988-1994
175
1999-2002
150
138
125
129
123
114
118
123
100
75
49.7 50.7 51.3
50
25
0
Total
Cholesterol
Carroll MD et al. JAMA. 2005;294:1773-1781.
HDLCholesterol
LDLCholesterol
Triglycerides
3
LDL-C and CV Risk
3.7
2.9
30 mg/dL
Relative
Risk for
2.2
Coronary
Heart
1.7
Disease
(log scale)
30 mg/dL
30 mg/dL
30 mg/dL
1.3
1.0
40
70
100
130
160
190
LDL-Cholesterol (mg/dL)
Grundy SM et al. Circulation. 2004; 110:227-239.
4
Cholesterol Treatment
Trialists’ Collaborators
 Meta-analysis,14 randomized controlled trials (n=90,056)
Primary
Prevention
(no CHD)
Major Vascular Events
(per 1 mmol/L LDL-C reduction)
Control
Statin
10.6
Seconday
Prevention
(Post-MI)
8.5
26.9
21.2
0
5
10
Both comparisons, P<0.001
Baigent C et al. Lancet. 2005;366:1267-1278.
15
20
25
30
Event Rate (% )
5
Lipid-Lowering Therapies
Statins
(atorvastatin, fluvastatin, lovastatin,
pravastatin, rosuvastatin, simvastatin)
Bile Acid Sequestrants
(colesevelam, cholestyramine, colestipol)
Nicotinic Acid
Fibric Acid Derivatives
LDL-C
HDL-C
TG
 18-63%
 5-15%
 7-30%
 15-30%
 3-5%
0 or 
 5-25%
 15-35%
 20-50%
 5-20 or   10-20%
 20-50%
(gemfibrozil, fenofibrate)
Cholesterol Absorption
Inhibitor (ezetimibe)
Omega-3 fatty acids
 18%
 1%
 7%
?
 9%
 45%
(prescription strength only)
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.
6
Mechanism of Action – HMG CoA
Reductase Inhibitors
Acetyl CoA
HMG-CoA
Competitive
Inhibition
Mevalonate
Cholesterol
production
 Expression
of LDL
receptors
 LDL,
VLDL,
and IDL
particles
HMG CoA
Reductase
Inhibitors
(Statins)
 Cholesterol
production
LDL Lowering
7
STELLAR Trial
Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin
 6-week, parallel groups, open-label study (n=2431)
% LDL-C Change from Baseline
Pravastatin
Simvastatin
Atorvastatin
Rosuvastatin
0
-10
-20
-30
-40
-20.1
-24.4
-29.7
10mg
-28.3
20mg
-35.0
-38.8
-36.8
40mg
80mg
-42.6
-50
-45.8
-45.8
-47.8
-51.1
-60
Jones PH et al. Am J Cardiol. 2003;92:152-160.
-52.4
-55.0
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Landmark Statin-based Outcome Trials
Trial
LDL-C (mg/dL)
Primary Endpoint/
CV Event Rate (%)
Baseline
Treatment
Placebo
Statin
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
Secondary
Prevention
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.
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
P<0.0001
P<0.0001
P=0.054
Cannon CP et al. J Am Coll Cardiol. 2006;48:438-445.
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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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Mechanism of Action – Bile Acid
Sequestrants
Bile Acid
Sequestrants
 Hepatic Bile Acid Pool
 Hepatic Bile Acid Synthesis
from Cholesterol
 Intrahepatic
Cholesterol Pool
 HMG-CoA Reductase Expression
 LDL Receptors
 VLDL Production / Secretion
 LDL Production
 LDL Clearance
 Plasma LDL-C
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Bile Acid Sequestrants
(colestipol, colesevelam, cholestyramine)
Provide modest reductions in LDL-C
May increase triglyceride values, especially
in patients with baseline hypertriglyceridemia
Avoid systemic toxicities
Some can bind the absorption of other drugs
when administered simultaneously
Primary 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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Mechanism of Action – Fibric Acid
Derivatives
Liver
Fibric
Acids
(Fibrates)
VLDL
ApoB
HDL
LDL
TG
ApoB
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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.
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 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
Rubins HB et al. N Engl J Med. 1999;341;410-418.
Cumulative incidence (%)
Veterans Affairs HDL Intervention Trial
(VA-HIT)
Death From CHD
and Nonfatal MI
25
22%
20
Placebo
15
10
Gemfibrozil
5
0
0
1
2
3
Year
4
5
6
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Fenofibrate Intervention and Event
Lowering in Diabetes (FIELD)
 9795 patients with type 2
diabetes
– CHD death +nonfatal MI
% Patients
 Randomized, double-blind
to placebo or fenofibrate
200mg daily x 5 yrs
 Primary endpoint:
15
Fenofibrate
Placebo
P=0.35
10
P=0.16
5
 Statin “drop-in” rate was
high
0
Primary
Endpoint
Secondary
Endpoint*
*Total CV events
Keech A et al. Lancet. 2005;366:1849–1861.
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Mechanism of Action - Niacin
Niacin
 Adipose tissue
FA mobilization
 FA synthesis/
esterification
 HDL-catabolism
receptor
 TG Synthesis
 Large TG-
rich VLDL
Small dense
 LDL-C
 Apo B lipoproteins
 HDL Apo A-I
 Apo B degradation
uptake/removal
 VLDL,  LDL-C
 HDL
Adapted from Kamanna VS, Kashyap ML. Curr Atheroscler Rep. 2000;2:36-46.
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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-C
Primary role is in addition to statin-based
therapy or in statin-resistant patients
No 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:
– LDL- C reductions:
319 and 318 mg/dL
58 and 41%
(P<0.01)
 Primary Endpoint: Change in mean carotid IMT
– Ezetimibe/Simvastatin
– Simvastatin
0.0111 mm
0.0058 mm
(P=0.29)
 Other Endpoints: Patients with CV Events
– Ezetimibe/Simvastatin
– Simvastatin
www.theheart.org.
12 of 357
9 of 363
(P=ns)
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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.
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