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American College of Cardiology Best Practice Quality Initiative Subcommittee

The Evidence for Current Cardiovascular Disease Prevention Guidelines: Cholesterol Management Evidence and Guidelines. American College of Cardiology Best Practice Quality Initiative Subcommittee and Prevention Committee.

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American College of Cardiology Best Practice Quality Initiative Subcommittee

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  1. The Evidence for Current Cardiovascular Disease Prevention Guidelines: Cholesterol Management Evidence and Guidelines American College of Cardiology Best Practice Quality Initiative Subcommittee and Prevention Committee

  2. Classification of Recommendations and Levels of Evidence *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Even though randomized trials are not available, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. †In 2003, the ACC/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines and will allow queries at the individual recommendation level.

  3. Icons Representing the Classification and Evidence Levels for Recommendations I I I IIa IIb III IIa IIb III IIa IIb III A B C I I I IIa IIb III IIa IIb III IIa IIb III A B C I I I IIa IIb III IIa IIb III IIa IIb III A B C I I I IIa IIb III IIa IIb III IIa IIb III A B C

  4. Evidence for Current Cardiovascular Disease Prevention Guidelines Cholesterol, Cholesterol Therapies, and Cholesterol Guidelines

  5. Lipoprotein Classes Chylomicrons,VLDL, and their catabolic remnants LDL HDL > 30 nm 20–22 nm 9–15 nm Potentially pro-inflammatory Potentially anti-inflammatory Sources: P. Barter. Role of Lipoproteins in Inflammation presentation, 2001. Available at http://www.lipidsonline.org/slides/slide01.cfm?&tk=18&dpg=3&x=293&43416. Doi H et al. Circulation 2000;102:670-676 Colome C et al. Atherosclerosis 2000;149:295-302 Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994

  6. (-) Role of Lipoproteins in Atherogenesis High plasmaLDL Endothelialinjury HDL LDL+VLDL LDL infiltrationinto intima Adherenceof platelets LCATAPO-A1 Releaseof PDGF Oxidativemodificationof LDL Liver Othergrowthfactors +Macrophages Foam cells Fatty streak Cholesterolexcreted Advancedfibrocalcificlesion APO-A1=Apolipoprotein A1, HDL=High density lipoprotein, LCAT=Lecithin cholesterol acyltransferase, LDL=Low density lipoprotein, PDGF=Platelet-derived growth factor, VLDL=Very low density lipoprotein

  7. Attributable Risk Factors for a First Myocardial Infarction INTERHEART Study 100 90 80 60 50 PAR (%) 36 33 40 20 18 20 12 14 10 7 0 Hyper-tension Smoking Fruits/Veg Exercise Alcohol Abdominal obesity Psycho-social Lipids All 9 risk factors Diabetes Lifestyle factors n=15,152 patients and 14,820 controls in 52 countries MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors) Source: Yusuf S et al. Lancet. 2004;364:937-952

  8. Change in Total Cholesterol Levels in the United States Over Time National Health and Nutrition Examination Survey (NHANES) 100% 90% 80% 70% Total Cholesterol mg/dl (mmol/L)age-adjusted percentage 60% 50% >240 mg/dL (>6.21 mmol/L) 40% 200-240 mg/dL (5.17-6.21 mmol/L) 30% <200 mg/dL (<5.17 mmol/L) 20% 10% 0% Source: Ford ES et al. Circulation 2009;120:1181-1188

  9. Coronary Heart Disease Risk According to LDL-C Level 3.7 2.9 2.2 1.7 1.3 1.0 Relative Risk for Coronary Heart Disease (Log Scale) 40 70 100 130 160 190 LDL-Cholesterol (mg/dL) CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol Source: Grundy S et al. Circulation 2004;110:227-239

  10. Therapies to Lower Levels of LDL-C Class Drug(s) Atorvastatin (Lipitor) Fluvastatin (Lescol XL) Lovastatin (Mevacor) Pitavastatin (Livalo) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor) 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors [Statins] Bile acid sequestrants Cholestyramine (Questran) Colesevelam (Welchol) Colestipol (Colestid) Cholesterol absorption inhibitor Ezetimibe (Zetia) Nicotinic acid Niacin Dietary Adjuncts Soluble fiber Soy protein Stanol esters

  11. HMG-CoA Reductase Inhibitor: Mechanism of Action Inhibition of the cholesterol biosynthetic pathway Squalene synthase Dolichol HMG-CoA Reductase Acetyl CoA HMG- CoA Farnesyl pyrophosphate Mevalonate Squalene Cholesterol Farnesyl- transferase E,E,E-Geranylgeranyl pyrophosphate Farnesylated proteins Geranylgeranylated proteins Ubiquinones

  12. HMG-CoA Reductase Inhibitor: Mechanism of Action VLDLR LDL VLDL Cholesterol synthesis Apo B LDL receptor (B–E receptor) synthesis LDL-R–mediated hepatic uptake of LDL and VLDL remnants Apo E Serum LDL-C Intracellular Cholesterol Apo B Serum VLDL remnants Serum IDL Hepatocyte Systemic Circulation The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which stimulates upregulation of the LDL receptor and increases uptake of non-HDL particles from the systemic circulation HDL=High density lipoprotein, LDL=Low density lipoprotein Source: McKenney JM. Selecting Successful Lipid-lowering Treatment presentation, 2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=4.

  13. HMG-CoA Reductase Inhibitor: Dose-Dependent Effect 28 12 Lovastatin 20/80* Pravastatin 20/40* 27 6 35 12 Simvastatin 20/80* Fluvastatin 20/80* 19 12 37 18 Atorvastatin 10/80* 0 10 20 30 40 50 60 The Rule of 6’s 46 6 Rosuvastatin 10/20† 32 11 Pitavastatin 1/4‡ Each doubling of the statin dose produces an approximate 6% reduction in the LDL-C level Sources: *Illingworth DR. Med Clin North Am 2000;84-23-42 †Crestor Package Insert. http://www1.astrazeneca-us.com/pi/crestor.pdf‡Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf

  14. HMG-CoA Reductase Inhibitor: Reduction in LDL-C Statin 10 mg/d 20 mg/d 40 mg/d 80 mg/d Atorvastatin 69 (37) 80 (43) 91 (49) 102 (55) Fluvastatin 29 (15) 39 (21) 50 (27) 61 (33) Lovastatin‡ 39 (21) 54 (29) 68 (37) 83 (45) Pravastatin 37 (20) 45 (24) 53 (29) 62 (33) Rosuvastatin§ 80 (43) 90 (48) 99 (53) 108 (58) Simvastatin 51 (27) 60 (32) 69 (37) 78 (42) A meta-analysis of 164 trials*†‡ *Standardized to LDL-C 186 mg/dL (mean concentration in trials) before Rx.† Independent of pre-Rx LDL-C ‡Maximum dose of 80 mg/day administered as two 40-mg tablets §Not FDA approved at 80 mg/day #Data presented as absolute reductions in LDL-C* (mg/dL) and percent reductions in LDL-C (in parentheses) ‡Although not included in this analysis, pitavastatin would be expected to achieve a 32%, 36%, and 43% mean reduction in LDL-C levels at the 1 mg, 2 mg, and 4 mg daily doses, respectively FDA=Food and Drug Administration, LDL-C=Low density lipoprotein cholesterol, Rx=Treatment Sources: Law MR et al. BMJ 2003;326:1423-1427 Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf

  15. HMG-CoA Reductase Inhibitor: Chronological Order of Event Driven Trials 1994 4S 2002 PROSPER 1995 WOSCOPS 2002 ALLHAT - LLA 1996 CARE 2002 ASCOT - LLA 1998 AFCAPS/TEXCAPS 2004 PROVE - IT 1998 LIPID 2004 A to Z 2001 MIRACL 2005 TNT 2002 HPS 2005 IDEAL 2008 JUPITER Study populations: Primary prevention Acute coronary syndromes (Secondary prevention) Chronic coronary heart disease (Secondary prevention) 2010 SEARCH

  16. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention West of Scotland Coronary Prevention Study (WOSCOPS) 6,595 men with moderate hypercholesterolemia randomized to pravastatin (40 mg) or placebo for 5 years A statin provides significant benefit in those with average cholesterol levels 31% RRR 9 7.5 6 5.3 Rate of MI or CHD death (%) 3 P<0.001 0 Placebo Pravastatin CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Shepherd J et al. NEJM 1995;333:1301-1307

  17. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention West of Scotland Coronary Prevention Study (WOSCOPS) Long-term follow-up at 5 and 10 years after conclusion of the study A statin provides long-term benefit in those with average cholesterol levels RRR=27%, p<0.001 Risk of MI or CHD death (%) RRR=18%, p<0.02 CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Ford I et al. NEJM 2007;357:1477-1486

  18. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS) 6,605 patients with average LDL-C levels randomized to lovastatin (20-40 mg) or placebo for 5 years A statin provides benefit in those with average LDL-C levels 37% RRR 5.5 6 4 3.5 Rate of MI, unstable angina, or SCD (%) 2 P<0.001 0 Placebo Lovastatin LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RRR=Relative risk reduction, SCD=Sudden cardiac death Source: Downs JR et al. JAMA 1998;279:1615–1622

  19. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention RR, 0.99; P=0.88 1 2 3 4 5 6 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Arm (ALLHAT-LLA) 10,355 patients with HTN and >1 CHD risk factor randomized to pravastatin (40 mg) or usual care for 5 years The failure to demonstrate benefit with a statin may be the result of a high rate of cross over 18 Pravastatin Usual care 15 12 32% cross-over among patients with CHD Cumulative rate % 9 6 3 0 Years CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk Source: ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007

  20. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA) 10,305 patients with HTN randomized to atorvastatin (10 mg) or placebo for 5 years A statin provides significant benefit in moderate- to high-risk individuals by lowering LDL-C levels below current goals 4 Atorvastatin 90 mg/dl* Placebo 126 mg/dl* 3 36% RRR Cumulative incidence of MI and fatal CHD (%) 2 1 P=0.0005 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Follow-up (yr) *Post-treatment LDL-C level CHD=Coronary heart disease, HTN=Hypertension, LDL-C=Low density lipoprotein cholesterol, RRR=Relative risk reduction Source: Sever PS et al. Lancet. 2003;361:1149-1158

  21. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Relationship between LDL-C levels and event rates in select primary prevention statin trials 10 Statin 8 Placebo WOSCOPS WOSCOPS 6 AFCAPS AFCAPS CHD event rate (%) 4 ASCOT 2 ASCOT 0 P=0.0019 –1 75 95 115 135 155 175 195 55 LDL cholesterol (mg/dL) AFCAPS= Air Force/Texas Coronary Atherosclerosis Prevention Study, ASCOT= Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, LDL-C=Low density lipoprotein cholesterol, WOSCOPS= West of Scotland Coronary Prevention Study Source: O’Keefe JH Jr et al. JACC 2004;43:2142-2146

  22. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial 7,832 men (age 40-70 years) and postmenopausal women (up to age 70 years) with total cholesterol levels of 220-270 mg/dL randomized to pravastatin (10-20 mg) or placebo for 5.3 years A statin provides benefit in those with high cholesterol levels 33% RRR 6 5.0 4 Number of adverse CV events* per 1000 person years 3.3 2 P=0.01 0 Placebo Pravastatin *Composite of cardiac and sudden death, myocardial infarction, angina, and cardiac or vascular intervention CV=Cardiovascular Source: Nakamura H et al. Lancet 2006;368:1155-63

  23. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) 17,802 men (>50 years) and women (>60 years) with LDL-C <130 mg/dL and hs-CRP >2 mg/L randomized to rosuvastatin (20 mg) or placebo for up to 5 years* A statin provides benefit in those with elevated hs-CRP levels 0.08 Rosuvastatin Placebo Cumulative incidence of CV death, MI, stroke, hospitalization for unstable angina, and arterial revascularization 44% RRR 0.04 P<0.00001, NNT=25 0.00 0 1 2 3 4 Follow-up (years) *The study was stopped prematurely after 1.9 years CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction Ridker PM et al. NEJM 2008;359:2195-2207

  24. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention 15 10 5 0 Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial 3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo for 16 weeks Acute intensive statin therapy provides significant CV benefit 17.4% Placebo 15 14.8% Atorvastatin 10 Combined CV event rate (%)* 5 RR=0.84, P=0.048 0 0 4 8 12 16 Weeks *Includes death, MI resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. ACS=Acute coronary syndrome, CV=Caradiovascular Source: Schwartz GG et al. JAMA 2001;285:1711-1718

  25. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study 4,162 pts with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months Acute intensive statin therapy provides significant CV benefit 30 16% RRR Pravastatin 25 Atorvastatin 20 Recurrent MI, cardiac death, UA, revascularization, or stroke 15 10 5 P=0.005 0 3 6 9 12 15 18 21 24 27 30 Follow-up (months) ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction, UA=Unstable angina Source: Cannon CP et al. NEJM 2004;350:1495-1504

  26. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Aggrastat to Zocor (A to Z) Trial 4,162 patients with an ACS randomized to simvastatin (80 mg) or simvastatin (20 mg) for 24 months Acute intensive statin therapy does not provide CV benefit 20 Placebo/Simvastatin 20 mg/day 15 Cumulative event rate (%)* Simvastatin 40/80 mg/day 10 5 HR=0.89, P=0.14 0 0 4 8 12 16 20 24 Time from randomization (months) *Includes CV death, MI, readmission for an ACS, and CVA ACS=Acute coronary syndrome, CV=Cardiovascular, CVA=Cerebrovascular accident, MI=Myocardial infarction Source: de Lemos JA et al. JAMA 2004;292:1307-1316

  27. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Scandinavian Simvastatin Survival Study (4S) 4,444 patients with angina pectoris or previous MI randomized to simvastatin (20-40 mg) or placebo for 5.4 years A statin provides significant benefit in those with average LDL-C levels 30% RRR 11.5 12 8.2 8 Mortality (%) 4 P<0.001 0 Placebo Simvastatin LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RRR=Relative risk reduction Source: 4S Group. Lancet 1994;344:1383–1389

  28. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Cholesterol and Recurrent Events (CARE) Study 4,159 patients with a history of MI randomized to pravastatin (40 mg) or placebo for 5 years A statin provides significant benefit in those with average cholesterol levels 24% RRR 15 13.2 10.2 10 Rate of MI or CHD death (%) 5 P=0.003 0 Placebo Pravastatin CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Srouce: Sacks FM et al. NEJM 1996;335:1001–1009

  29. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study 9,014 patients with a history of MI or hospitalization for unstable angina randomized to pravastatin (40 mg) or placebo for 6.1 years A statin provides significant benefit across a broad range of cholesterol levels 24% RRR 8.3 9 6.4 6 CHD Death (%) 3 P<0.001 0 Placebo Pravastatin CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: LIPID Study Group. NEJM 1998;339:1349–1357

  30. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention 0.4 0.6 0.8 1.0 1.2 1.4 Heart Protection Study (HPS) Event Rate Ratio (95% CI) Statin Better Statin Worse 0.76 (0.72–0.81) P<0.0001 A statin provides significant CV benefit regardless of baseline LDL-C level CAD=Coronary artery disease, CI=Confidence interval, CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol Source: HPS Collaborative Group. Lancet 2002;360:7-22

  31. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) 5,804 patients aged 70-82 years with a history of, or risk factors for, vascular disease randomized to pravastatin (40 mg) or placebo for 3.2 years A statin provides CV benefit in older men 20 Placebo CHD death, non-fatal MI, stroke (%) 10 Pravastatin 15% RRR, P=0.014 0 0 1 2 3 4 Years CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: Shepherd J et al. Lancet 2002;360:1623-1630

  32. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention 0 1 2 3 4 5 6 Treating to New Targets (TNT) Trial 10,001 patients with stable CHD randomized to atorvastatin (80 mg) or atorvastatin (10 mg) for 4.9 years High-dose statin therapy provides benefit in chronic CHD 0.15 22% RRR Atorvastatin (10 mg) 0.10 Major CV Event* (%) Atorvastatin (80 mg) 0.05 P<0.001 0.00 Years *Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: LaRosa JC et al. NEJM 2005;352:1425-35

  33. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial 8,888 patients with a history of acute MI randomized to atorvastatin (80 mg) or simvastatin (20 mg) for 5 years High-dose statin therapy does not provide CV benefit after a MI 12 Simvastatin (20 mg) 8 Atorvastatin (80 mg) Cumulative Hazard (%) 4 HR=0.89, P=0.07 0 1 2 3 4 5 Years Since Randomization *Includes coronary death, hospitalization for nonfatal acute MI, or cardiac arrest with resuscitation CV=Cardiovascular, HR=Hazard ratio, MI=Myocardial infarction Source: Pedersen TR et al. JAMA 2005;294:2437-2445

  34. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Relationship between LDL-C levels and event rates in secondary prevention statin trials of patients with stable CHD 30 4S Statin Placebo 25 4S 20 Event (%) LIPID LIPID 15 CARE CARE HPS HPS 10 TNT (atorvastatin 10 mg/d) TNT (atorvastatin 80 mg/d) 5 0 0 70 90 110 130 150 170 190 210 LDL-C (mg/dL) CARE=Cholesterol and Recurrent Events Trial, CHD=Coronary heart disease, HPS=Heart Protection Study, LDL-C=Low density lipoprotein cholesterol, LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease, 4S=Simvastatin Survival Study, TNT=Treating to New Targets Source: LaRosa JC et al. NEJM 2005;352:1425-1435

  35. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) 12,064 patients with a history of MI randomized to simvastatin (80 mg) or simvastatin (20 mg) for a mean of 6.7 years High-dose statin therapy does not provide CV benefit after a MI * *Includes coronary death, myocardial infarction, stroke, or arterial revascularization CHD=Coronary heart disease, MI=Myocardial infarction Source: SEARCH Collaborative Group. Lancet 2010;376:1658-1669

  36. HMG-CoA Reductase Inhibitor Evidence: Degree of Benefit in Prevention Types Meta-analysis of randomized controlled trials comparing risk reductions between primary and secondary prevention patients CABG=Coronary artery bypass graft surgery, CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, PCI=Percutaneous coronary intervention Source: Thavendiranathan P et al. Arch Intern Med 2006;166:2307-2313

  37. HMG-CoA Reductase Inhibitor Evidence: Effect of Intensive Therapy Trial Population Duration (years) LDL-C Reduction (mg/dL) RR in Primary End Point (%) RR in MI or CHD Death (%) PROVE IT-TIMI 22 ACS (N = 4162) 2 33 16 16 A to Z ACS (N = 4497) 2 14 11 15 TNT Stable CAD (N =10,001) 5 24 22 21 IDEAL Stable CAD (N = 8888) 5 23 11 11 Magnitude of event reduction among trials of intensive statin therapy Note: SI conversion factor: To convert LDL-C to mmol/L, multiply by 0.0259 ACS=Acute coronary syndrome, CAD=Coronary artery disease, CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RR=Relative reduction Source: Cannon CP et al. JAMA 2005;294:2492-2494

  38. HMG-CoA Reductase Inhibitor Evidence: Effect of Intensive Therapy 21% relative risk reduction per mmol/L Statin 16% relative risk reduction per 0.5 mmol/L More statin Cholesterol Treatment Trialists’ (CTT) Collaboration Meta-analysis of 169,138 patients randomized to at least 2 years of statin therapy Control 20 15 Five year risk of a major vascular event, % 10 0 0 1 2 3 4 5 LDL cholesterol level (mmol/L) There is a proportionate reduction in CV events with greater LDL-cholesterol reduction CV=Cardiovascular, LDL=Low density lipoprotein Source: Cholesterol Treatment Trialists’ Collaboration. Lancet 2010;376:1670-1681

  39. HMG-CoA Reductase Inhibitor: Adverse Effects 74,102 subjects in 35 randomized clinical trials with statins • 1.4% incidence of elevated hepatic transaminases (1.1% incidence in control arm) • Dose-dependent phenomenon that is usually reversible Hepatocyte • 15.4% incidence of myalgias* (18.7% incidence in control arm) • 0.9% incidence of myositis (0.4% incidence in control arm) • 0.2% incidence of rhabdomyolysis (0.1% incidence in control arm) Skeletal myocyte *The rate of myalgias leading to discontinuation of atorvastatin in the TNT trial was 4.8% and 4.7% in the 80 mg and 10 mg arms, respectively Source: Kashani A et al. Circulation 2006;114:2788-2797

  40. HMG-CoA Reductase Inhibitor: Adverse Effects Risk factors for the development of myopathy* *General term to describe diseases of muscles **Itraconazole, Ketoconazole †Erythromycin, Clarithromycin ‡Chronic renal insufficiency, especially from diabetes mellitus Source: Pasternak RC et al. Circulation 2002;106:1024-1028

  41. Bile Acid Sequestrant: Mechanism of Action Gall Bladder Liver  Cholesterol 7- hydroxylase • Conversion of cholesterol to BA • BA Secretion Bile Acid Enterohepatic Circulation Terminal Ileum • LDL Receptors • VLDL and LDL removal Reabsorption of bile acids • BA Excretion  LDL-C BA=Bile acid, LDL-C=Low density lipoprotein cholesterol, VLDL=Very low density lipoprotein

  42. Bile Acid Sequestrant Evidence: Efficacy at Reducing LDL-C LDL-C HDL-C TG 15 10 10 5 5 † 3 0 0 % Change from baselineat week 24 -1 -5 -10 Placebo Colesevelam 3.8 grams/day -15 * -15 -20 *P<0.001 vs placebo †P=0.04 vs placebo HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride Source: Insull W et al. Mayo Clin Proc 2001;76:971-982

  43. Bile Acid Sequestrant Evidence: Primary Prevention Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) 3,806 men with primary hypercholesterolemia randomized to cholestyramine (24 grams) or placebo for 7.4 years A bile acid sequestrant provides benefit in those with high cholesterol levels 19% RRR 8.6 9 7.0 6 Rate of MI or CHD death (%) 3 P<0.05 0 Placebo Cholestyramine CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: The LRC-CPPT Investigators. JAMA 1984;251:351-364

  44. Ezetimibe: Mechanism of Action Production in liver Absorption from intestine Dietary cholesterol Bloodstream LDL-C VLDL Biliary cholesterol Cholesterolsynthesis Chylomicrons Fecal sterols and neutral sterols

  45. Ezetimibe Evidence: Efficacy at Reducing LDL-C Placebo Ezetimibe 10 mg 892 patients with primary hypercholesterolemia randomized to ezetimibe (10 mg) or placebo for 12 weeks LDL-C HDL-C Triglycerides +5.7 +5 +1.3 +0.4 0 –1.6 –5 Mean % change frombaseline to week 12 –5.7 –10 –15 –16.9* –20 *p<0.01 compared to placebo HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Dujovne CA et al. Am J Cardiol 2002;90:1092-1097

  46. Dietary Adjuncts Evidence: Efficacy at Reducing LDL-C LDL-C=Low density lipoprotein cholesterol Sources: Kwiterovich Jr PO. Pediatrics 1995;96:1005-1009 Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214 Miettinen TA et al. Ann Med 2004;36:126-134

  47. CHD Risk According to HDL-C Level Framingham Study 4.0 4.0 3.0 CHD risk ratio 2.0 2.0 1.0 1.0 0 65 25 45 HDL-C (mg/dL) CHD=Coronary heart disease, HDL-C=High-density lipoprotein cholesterol Source: Kannel WB. Am J Cardiol 1983;52:9B–12B

  48. Nicotinic Acid: Mechanism of Action Mobilization of FFA Apo B Serum VLDL results in reduced lipolysis to LDL VLDL VLDL TG synthesis Serum LDL VLDL secretion LDL HDL Hepatocyte Systemic Circulation Apo B Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in reduced LDL cholesterol levels and increased HDL cholesterol levels FFA=Free fatty acid, HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride, VLDL=Very low density lipoprotein Source: McKenney JM. Selecting Successful Lipid-lowering Treatments presentation, 2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=14

  49. Nicotinic Acid Evidence: Effect on Lipid Parameters 30 20 10 0 -10 -20 -30 -40 -50 30% 30% 26% HDL-C 22% 15% 10% –9% Mean change from Baseline –14% –5% –17% –21% –22% LDL-C –11% –28% –35% Triglyceride –39% –44% Dose (mg) 500 1000 1500 2000 2500 3000 HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride Source: Goldberg A et al. Am J Cardiol 2000;85:1100-1105

  50. Nicotinic Acid Evidence: Secondary Prevention Coronary Drug Project (CDP) 8,341 men with previous myocardial infarction randomized to nicotinic acid (3 grams) or placebo for 15 years Niacin provides long-term benefit following a MI 100 90 80 70 Survival (%) Nicotinic Acid 60 Nicotinic acid stopped 50 Placebo 40 P=0.0012 16 14 12 10 6 8 4 0 2 Years of follow-up MI=Myocardial infarction Source: Canner PL et al. JACC 1986;8:1245–1255

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