1. 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. 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. 3 NHANES: Serum Lipids and Lipoproteins in Adults Carroll MD et al. JAMA. 2005;294:1773-1781.

4. 4 LDL-C and CV Risk Grundy SM et al. Circulation. 2004; 110:227-239. 30 mg/dL 30%  30%  1.0 1.3 1.7 2.2 2.9 3.7 4070100130160190 LDL-Cholesterol (mg/dL) Relative Risk for Coronary Heart Disease (log scale)

5. 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. 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. LDL-CHDL-CTG 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%

7. 7 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

8. 8 STELLAR Trial Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin Jones PH et al. Am J Cardiol. 2003;92:152-160.  6-week, parallel groups, open-label study (n=2431)

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. Trial LDL-C (mg/dL) Primary Endpoint/ CV Event Rate (%) BaselineTreatmentPlaceboStatin Secondary Prevention 4S18812228.019.4 LIPID15011215.712.3 CARE1399813.210.2 Primary & Secondary Prevention HPS1329324.419.9 PROSPER1479716.214.1 Primary Prevention WOSCOPS1921597.55.3 AFCAPS1501155.53.5 ASCOT133903.01.9 CARDS118779.05.8

10. 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 Cannon CP et al. J Am Coll Cardiol. 2006;48:438-445. P=0.054 P<0.0001

11. 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. 12  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

13. 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. 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. 15 TG HDL Lipoprotein lipase VLDL ApoB LDL ApoB Fibric Acids (Fibrates) Liver Mechanism of Action – Fibric Acid Derivatives

16. 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. 17 Rubins 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 0123456 Year Cumulative incidence (%) Death From CHD and Nonfatal MI Placebo Gemfibrozil 22%

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

19. 19 Niacin  Adipose tissue FA mobilization  TG Synthesis  FA synthesis/ esterification  HDL-catabolism receptor  HDL Apo A-I uptake/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

20. 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. 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. 22 Mechanism of Action – Cholesterol Absorption Inhibitor

23. 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. 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/Simvastatin0.0111 mm –Simvastatin0.0058 mm (P=0.29)  Other Endpoints: Patients with CV Events –Ezetimibe/Simvastatin12 of 357 –Simvastatin9 of 363 (P=ns) www.theheart.org.

25. 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.