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

1. 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

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. NHANES:Serum Lipids and Lipoproteins in Adults Carroll MD et al. JAMA. 2005;294:1773-1781.

4. LDL-C and CV Risk 30 mg/dL 30 mg/dL 30 mg/dL 30 mg/dL 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; 110:227-239.

5. Cholesterol Treatment Trialists’ Collaborators Meta-analysis,14 randomized controlled trials (n=90,056) Both comparisons, P<0.001 Baigent C et al. Lancet. 2005;366:1267-1278.

6. 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.

7. Acetyl CoA X HMG-CoA HMG-CoA Reductase HMG CoA Reductase Inhibitors (Statins) Competitive Inhibition Mevalonate  Expression of LDL receptors  Cholesterol production Cholesterol production LDL Lowering  LDL, VLDL, and IDL particles 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 (n=2431) Jones PH et al. Am J Cardiol. 2003;92:152-160.

9. 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.

10. 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.

11. 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.

12. 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 Clearance  Plasma LDL-C  LDL Production Mechanism of Action – Bile Acid Sequestrants

13. 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 (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.

15. Liver Fibric Acids (Fibrates) VLDL LDL ApoB ApoB HDL Lipoprotein lipase TG Mechanism of Action – Fibric Acid Derivatives

16. 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.

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 Death From CHD and Nonfatal MI 25 22% 20 Placebo 15 Cumulative incidence (%) Gemfibrozil 10 5 0 0 1 2 3 4 5 6 Year Rubins HB et al. N Engl J Med. 1999;341;410-418.

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 P=0.35 Fenofibrate 15 Placebo 10 P=0.16 % Patients 5 0 Primary Secondary Endpoint Endpoint* *Total CV events Keech A et al. Lancet. 2005;366:1849–1861.

19.  HDL  VLDL,  LDL-C • Small dense • LDL-C Mechanism of Action - Niacin Niacin  Adipose tissue FA mobilization  FA synthesis/ esterification  HDL-catabolism receptor  TG Synthesis  Large TG-rich VLDL  Apo B lipoproteins  Apo B degradation  HDL Apo A-I uptake/removal Adapted from Kamanna VS, Kashyap ML. Curr Atheroscler Rep. 2000;2:36-46.

20. 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 (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.

22. Mechanism of Action – Cholesterol Absorption Inhibitor

23. 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% (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.

25. 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.