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

1
LDL-C and CV RiskWhat We Know and Don't Know
Joseph J. Saseen, PharmD, FCCP, BCPS,
CLS Associate Professor Clinical Pharmacy and
Family Medicine University of Colorado Denver
2
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/
3
NHANESSerum Lipids and Lipoproteins in Adults
Carroll MD et al. JAMA. 20052941773-1781.
4
LDL-C and CV Risk
3.7
2.9
Relative Risk for Coronary Heart Disease (log
scale)
30? 30? 30? 30?
2.2
1.7
1.3
1.0
40
70
100
130
160
190
LDL-Cholesterol (mg/dL)
Grundy SM et al. Circulation. 2004 110227-239.
5
Cholesterol Treatment Trialists Collaborators

• Meta-analysis,14 randomized controlled trials
  (n90,056)

Both comparisons, Plt0.001
Baigent C et al. Lancet. 20053661267-1278.
6
Lipid-Lowering Therapies
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
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 20012852486-2497. Zetia package
insert. Merck/Schering-Plough Pharmaceuticals
2005. Crestor package insert. Astra-Zeneca
2005. Omacor package insert. Reliant
Pharmaceuticals 2005.
7
Mechanism of Action HMG CoA Reductase Inhibitors
8
STELLAR TrialStatin Therapies for Elevated Lipid
Levels Compared Across Doses to Rosuvastatin

• 6-week, parallel groups, open-label study (n2431)

Jones PH et al. Am J Cardiol. 200392152-160.
9
Landmark Statin-based Outcome Trials
Trial LDL-C (mg/dL) LDL-C (mg/dL) Primary Endpoint/CV Event Rate () Primary Endpoint/CV Event Rate ()
Trial Baseline Treatment Placebo Statin
Secondary Prevention 4S 188 122 28.0 19.4
Secondary Prevention LIPID 150 112 15.7 12.3
Secondary Prevention CARE 139 98 13.2 10.2
Primary Secondary Prevention HPS 132 93 24.4 19.9
Primary Secondary Prevention PROSPER 147 97 16.2 14.1
Primary Prevention WOSCOPS 192 159 7.5 5.3
Primary Prevention AFCAPS 150 115 5.5 3.5
Primary Prevention ASCOT 133 90 3.0 1.9
Primary Prevention CARDS 118 77 9.0 5.8
Jacobson TA et al. Arch Intern Med.
19981581977-1989. Heart Protection Study
Collaborative. Lancet. 20023607-22. Shepherd
J et al. Lancet. 2002 3601623-1630. Sever PS
et al. Lancet. 20033611149-58. Colhoun HM et
al. Lancet. 2004364685-696.
10
Patients with CHDIntensive Vs Moderate Statin
Therapy

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

Plt0.0001
Plt0.0001
P0.054
Cannon CP et al. J Am Coll Cardiol.
200648438-445.
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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.
20054589-118. Tandon V. Indian J Pharmacol.
20053777-85.
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Mechanism of Action Bile Acid Sequestrants
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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

14
Bile Acid Sequestrant Outcomes Data

• LRC-Primary Prevention Trial (n3086)
• Cholestyramine reduced fatal CHD non-fatal MI
  19 versus placebo over 7.4 yrs (7.0 vs 8.6,
  Plt0.05)
• FATS Trial (n146)
• Intensive LDL-C lowering in CHD patients using
  colestipol with lovastatin or niacin lowered CV
  event risk versus conventional therapy (HR0.27,
  0.10 to 0.77)

LRC-CPP Trial. JAMA. 1984251351-374. Brown G
et al. N Engl J Med. 1990 3231289-1298.
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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. 19873171237-1245.
17
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

Rubins HB et al. N Engl J Med. 1999341410-418.
18
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

P0.35
Fenofibrate
15
Placebo
10
P0.16
Patients
5
0
Primary
Secondary
Endpoint
Endpoint
Total CV events
Keech A et al. Lancet. 200536618491861.
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Mechanism of Action - Niacin
Niacin
? Adipose tissue FA mobilization
? FA synthesis/ esterification
? HDL-catabolism receptor
? TG Synthesis
? HDL Apo A-I uptake/removal
? Large TG-rich VLDL
? Apo B lipoproteins ? Apo B degradation
Adapted from Kamanna VS, Kashyap ML. Curr
Atheroscler Rep. 2000236-46.
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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

21
Nicotinic Acid Outcomes Data

• HATS Trial (n160)
• Simvastatin niacin reduced CV events versus
  placebo over 3 yrs in patients (2.6 vs 23.7,
  Plt0.05)
• Coronary Drug Project (n1119)
• 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 (n167)
• 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. 20013451583-1592.
JAMA .1975231360-381. Canner PL et al. J Am
Coll Cardiol. 198681245-1255. Taylor AJ et al.
Circulation. 20041103512-3517.
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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.
24
ENHANCE Results

• Significant differences in LDL-C reduction
• Baseline LDL-C values 319 and 318 mg/dL
• LDL- C reductions 58 and 41 (Plt0.01)
• Primary Endpoint Change in mean carotid IMT
• Ezetimibe/Simvastatin 0.0111 mm
• Simvastatin 0.0058 mm (P0.29)
• Other Endpoints Patients with CV Events
• Ezetimibe/Simvastatin 12 of 357
• Simvastatin 9 of 363 (Pns)

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
• gt10,000 patients who are stable after acute
  coronary syndrome
• Primary endpoint fatal and non-fatal CV event
• Results expected in 2011

www.clinicaltrials.gov.