The Evidence for Current Cardiovascular Disease Prevention Guidelines:

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 1 1

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.

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

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

Chylomicrons, VLDL, and their catabolic remnants
Lipoprotein Classes Chylomicrons, VLDL, and their catabolic remnants LDL HDL > 30 nm 20–22 nm 9–15 nm Classes of lipoproteins include LDL (low density lipoprotein), HDL (high density lipoprotein), VLDL (very low density lipoprotein), and chylomicrons. Potentially pro-inflammatory Potentially anti-inflammatory Sources: P. Barter. Role of Lipoproteins in Inflammation presentation, Available at Doi H et al. Circulation 2000;102: Colome C et al. Atherosclerosis 2000;149: Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:

Role of Lipoproteins in Atherogenesis
High plasma LDL Endothelial injury HDL (-) LDL + VLDL LDL infiltration into intima Adherence of platelets LCAT APO-A1 Oxidative modification of LDL Release of PDGF Liver Other growth factors + Macrophages Foam cells Fatty streak Pro-atherogenic lipoprotein particles such as LDL-C infiltrate the intima of the arterial wall and undergo oxidative changes. Accumulation of these atherogenic particles attract macrophages that engulf cholesterol, causing formation of foam cells and subsequent fatty streaks. This process injures the endothelium of the arterial wall, promoting adherence of platelets, release of PDGF, and development of an advanced fibrocalcific lesion. Anti-atherogenic particles such as HDL-C and apo-A1 promote reverse cholesterol transport and cholesterol efflux from foam cells. They also help to prevent oxidation of LDL-C and other atherogenic particles. Cholesterol excreted Advanced fibrocalcific lesion 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 6

Attributable Risk Factors for a First Myocardial Infarction
INTERHEART Study 100 90 80 60 50 PAR (%) 40 36 33 20 18 20 14 12 10 7 In this study of 15,152 patients, lipids had the highest population attributable risk for a first myocardial infarction among 9 risk factors for cardiovascular disease. Smoking Fruits/ Veg Exercise Alcohol Hyper- tension Diabetes Abdominal obesity Psycho- social Lipids All 9 risk factors 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:

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% mg/dL ( mmol/L) 30% <200 mg/dL (<5.17 mmol/L) 20% In this study, Ford and colleagues calculated the prevalence of favorable total cholesterol status by assigning participants to low risk status (total cholesterol < 5.17 mmol/L) using only the measurements of total cholesterol (treatment with cholesterol-lowering medications was not used in determining risk status). The age-adjusted estimates for the 4 time periods were 34.5%, 37.9%, 45%, and 48% indicating overall improvement in cholesterol levels over time. 10% 0% Source: Ford ES et al. Circulation 2009;120:

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) This graph demonstrates the relative risk for coronary heart disease relative to the LDL-C level. LDL-Cholesterol (mg/dL) CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol Source: Grundy S et al. Circulation 2004;110: 9

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

Inhibition of the cholesterol biosynthetic pathway
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 Statins inhibit the HMG-CoA reductase enzyme, leading to reduced hepatic intracellular cholesterol production. Farnesylated proteins Geranylgeranylated proteins Ubiquinones 11

HMG-CoA Reductase Inhibitor: Mechanism of Action
VLDL Cholesterol synthesis VLDLR LDL receptor (B–E receptor) synthesis Apo B LDL-R–mediated hepatic uptake of LDL and VLDL remnants Apo E Intracellular Cholesterol Serum LDL-C LDL Apo B Serum VLDL remnants Serum IDL Hepatocyte Statins decrease hepatic cholesterol synthesis, leading to an upregulation of LDL-C receptors on the surface of hepatocytes. This results in increased clearance of LDL-C particles from the serum. 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, Available at 12

HMG-CoA Reductase Inhibitor: Dose-Dependent Effect
The Rule of 6’s 37 19 35 27 28 18 12 6 10 20 30 40 50 60 Atorvastatin 10/80* Fluvastatin 20/80* Simvastatin 20/80* Pravastatin 20/40* Lovastatin 20/80* Rosuvastatin 10/20† 46 6 The recommended starting dose for each statin results in a mean reduction in the LDL-C level between 19% to 37%. Thereafter, each doubling of the dose results in an approximate 6% further lowering of the LDL-C level. Titration to the maximum approved dose produces a mean reduction of approximately 31% to 51%. There is marked variability in the potency of the available statin medications. In general, fluvastatin is regarded as the least potent and rosuvastatin is regarded as the most potent. Pitavastatin 1/4‡ 32 11 Each doubling of the statin dose produces an approximate 6% reduction in the LDL-C level Sources: *Illingworth DR. Med Clin North Am 2000; †Crestor Package Insert ‡Livalo Package Insert. 13

A meta-analysis of 164 trials*†‡
HMG-CoA Reductase Inhibitor: Reduction in LDL-C A meta-analysis of 164 trials*†‡ 78 (42) 69 (37) 60 (32) 51 (27) Simvastatin 108 (58) 99 (53) 90 (48) 80 (43) Rosuvastatin§ 62 (33) 53 (29) 45 (24) 37 (20) Pravastatin 83 (45) 68 (37) 54 (29) 39 (21) Lovastatin‡ 61 (33) 50 (27) 29 (15) Fluvastatin 102 (55) 91 (49) Atorvastatin 80 mg/d 40 mg/d 20 mg/d 10 mg/d Statin This meta-analysis of trials using statin therapy sought to evaluate the effect of available statins on LDL-C levels at different doses. The analysis demonstrated that the average reduction in LDL-C level achieved with statin therapy was 1.8 mmol/l (69 mg/dL). This translated into a reduction in the risk of ischemic heart disease by 60% and stroke by 17%. *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: Livalo Package Insert. 14

HMG-CoA Reductase Inhibitor:
Chronological Order of Event Driven Trials Study populations: Primary prevention Acute coronary syndromes (Secondary prevention) Chronic coronary heart disease (Secondary prevention) 1994 4S 2002 PROSPER 1995 WOSCOPS ALLHAT - LLA 1996 CARE ASCOT 1998 AFCAPS/TEXCAPS 2004 PROVE IT LIPID A to Z 2001 MIRACL 2005 TNT HPS IDEAL 2008 JUPITER Early statin trials evaluated patients with hypercholesterolemia in both the primary and secondary prevention settings. Subsequent trials extended this to patients with a broad range of cholesterol levels. The MIRACL trial was the first to evaluate the immediate effect of statins in the setting of an acute coronary syndrome. More recent trials have evaluated intensive LDL-C reduction in patients with acute coronary syndromes and chronic coronary heart disease. 2010 SEARCH 15

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 The WOSCOPS trial was one of the first trials to examine the effect of statins on cardiovascular events in individuals with hypercholesterolemia. This trial specifically randomized men (45-65 years old) with moderate hypercholesterolemia (total cholesterol of 272 ± 23 mg/dL) and no history of myocardial infarction to pravastatin (40 mg) or placebo. Pravastatin resulted in a 31% relative risk reduction in the rate of coronary heart disease death or nonfatal myocardial infarction, with no effect on the risk of death from non-cardiovascular causes. Placebo Pravastatin CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Shepherd J et al. NEJM 1995;333: 16

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 Five years after the WOSCOPS trial ended, 38.7% of those originally randomized to pravastatin and 35.2% of those originally randomized to placebo were being treated with a statin. Approximately 10 years after completion of the trial, the risk of death from coronary heart disease or nonfatal myocardial infarction was 10.3% in the placebo group and 8.6% in the pravastatin group. Over the entire follow-up period, the event rate was 15.5% in the placebo group and 11.8% in the pravastatin group. Benefit from pravastatin was also noted in the combined rate of death from coronary heart disease and hospitalization for coronary events, the rate of death from cardiovascular cause, and the rate of death from any cause over the entire follow-up period. Treatment with pravastatin resulted in no excess deaths from non-cardiovascular causes and no excess fatal or incident cancers. CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Ford I et al. NEJM 2007;357: 17

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 6 5.5 4 Rate of MI, unstable angina, or SCD (%) 3.5 The AFCAPS/TEXCAPS trial randomized 6605 men and women with average levels of total cholesterol (221 mg/dl) and LDL-C (150 mg/dl) and below average levels of HDL-C (36mg/dl) to lovastatin (20-40 mg) or placebo, along with dietary modification. Over a 5 year follow-up, there was a significant 37% relative risk reduction in the rate of myocardial infarction, unstable angina, or sudden cardiac death in those receiving lovastatin. 2 P<0.001 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 18

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 RR, 0.99; P=0.88 Pravastatin Usual care 15 12 32% cross-over among patients with CHD Cumulative rate % 9 6 3 The ALLHAT-LLA trial (a sub study of the larger ALLHAT trial) sought to determine whether statin therapy compared to usual care would reduce all cause mortality in older, moderately hypercholesterolemic, hypertensive patients with at least 1 other CHD risk factor. The baseline mean levels of total cholesterol, LDL-C, HDL-C, and triglyceride were 224 mg/dL, 146 mg/dL, 48 mg/dL, and 152 mg/dL, respectively The trial included diverse and often underrepresented patient populations (49% were women, 38% were African American, and 23% were Hispanic). A total of 14% had a history of coronary heart disease and 35% had type II diabetes. There was no statistical difference in the primary end point (mortality). There was only a 9% total cholesterol difference between the treatment and placebo arms which may have been related to the large cross-over among patients to statin therapy. Years CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk Source: ALLHAT Collaborative Research Group. JAMA 2002;288: 19

Cumulative incidence of MI and fatal CHD (%)
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 mg/dl* 3 36% RRR Cumulative incidence of MI and fatal CHD (%) 2 1 P=0.0005 The ACSCOT-LLA trial (a substudy of the larger ASCOT trial) sought to assess the benefit of cholesterol reduction in hypertensive patients not deemed hypercholesterolemic (total non-fasting cholesterol <250mg/dl) by conventional means, but with at least three other cardiovascular risk factors. Patients were randomized to treatment with atorvastatin (10 mg) or placebo and the primary endpoint was non-fatal MI and fatal CHD by an intention to treat analysis. The study was stopped after 3.3 years due to a significant reduction in the primary endpoint in the atorvastatin arm compared to placebo (HR=0.64 [95% CI ], p=0.0005). Importantly, while benefit was noted in the first year of treatment, there was no significant difference in death between the two arms. 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: 20

LDL cholesterol (mg/dL)
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 CHD event rate (%) AFCAPS 4 ASCOT 2 ASCOT Data from the main primary prevention trials (prior to publication of the MEGA and JUPITER trials) are displayed here. P=0.0019 –1 55 75 95 115 135 155 175 195 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:

Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial 7,832 men (age years) and postmenopausal women (up to age 70 years) with total cholesterol levels of 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 Number of adverse CV events* per 1000 person years 4 3.3 The MEGA trial sought to evaluate the effect of low dose pravastatin as compared to placebo in a heterogeneous primary prevention population in Japan. Pravasatin was shown to have a significant reduction in a composite of adverse CV events. 2 P=0.01 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:

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 for unstable angina, and arterial revascularization death, MI, stroke, hospitalization 44% RRR 0.04 The JUPITER trial sought to evaluate the effect of rosuvastatin (as compared to placebo) in a primary prevention population with a baseline LDL-C level <130 mg/dL that was screened to identify patients with a baseline hs-CRP level >2 mg/dL. Treatment with rosuvastatin was associated with an ~44% relative risk reduction in a composite CV end point. The number needed to treat (NNT) to reduce 1 event was 25 for the primary endpoint. P< , NNT=25 0.00 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:

HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention
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% 5 10 15 15 Placebo 14.8% Atorvastatin 10 Combined CV event rate (%)* 5 RR=0.84, P=0.048 The MIRACL trial was the first large scale study to evaluate the effects of acute intensive statin therapy in the secondary prevention setting. Compared to placebo, treatment with atorvastatin (80 mg) within 96 hours of an acute coronary syndrome resulted in a 16% relative risk reduction in the primary end point (death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or objective evidence of recurrent symptomatic myocardial ischemia requiring emergency rehospitalization) in the first 16 weeks of treatment. There were no significant differences in the risk of death, nonfatal myocardial infarction, or cardiac arrest in the two arms of the study. The difference in the primary endpoint was driven by a lower risk of symptomatic ischemia requiring emergency rehospitalization (6.2% vs. 8.4%; RR, 0.74; 95% CI, ; P =0.02). Treatment with atorvastatin resulted in a mean decrease in LDL-C from 124 mg/dL to 72 mg/dL. There was a significant increase in hepatic transaminases >3x the upper limit of normal with atorvastatin as compared to placebo (2.5% vs 0.6%; P<.001). 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: 24

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 The PROVE IT-TIMI 22 trial was designed to assess the effects of early statin therapy in individuals with an acute coronary syndrome. In a head-to-head comparison of statin regimens, patients were randomized to a high dose potent statin (atorvastatin 80 mg) or a moderate dose less potent statin (pravastatin 40 mg) over a mean follow-up of 24 months to determine if intensive statin therapy was associated with a lower event rate. Use of atorvastatin and pravastatin resulted in on-treatment mean LDL-C levels of 62 mg/dL and 95 mg/dL, respectively. The primary end point (a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, recurrent revascularization, or stroke) occurred in 22.4% of individuals on atorvastatin vs. 26.3% of individuals on pravastatin, p= This effect of intensive statin therapy set a new benchmark for aggressive early LDL-C lowering in acute coronary syndromes. 5 P=0.005 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: 25

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 The A to Z trial sought to determine whether treatment with a low dose statin regimen would provide similar risk reduction in patients with an ACS as a high dose statin regimen (similar to that used in the PROVE IT-TIMI 22 and MIRACL trials). The high dose statin regimen consisted of treatment with simvastatin at 40 mg/day for one month, followed by an increase to 80 mg/day thereafter. The low dose statin regimen consisted of treatment with placebo for 4 months, followed by simvastatin at 20 mg/day thereafter. There was no statistical difference in the primary end point between the two treatment strategies; however, there was a trend towards a reduced event rate in the high dose statin regimen at the end of the 24 month follow-up. Unfortunately, the high dose statin regimen was associated with nine cases of statin-induced myopathy. 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: 26

Scandinavian Simvastatin Survival Study (4S)
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 The 4S trial was a landmark study that sought to evaluate the effect of statin therapy in secondary prevention. A total of 4,444 men and women with angina or prior MI and serum cholesterol levels of mmol/L ( mg/dL) were randomized to simvastatin (20-40 mg) or placebo for greater than 5 years. Treatment with simvastatin resulted in a 30% relative risk reduction in all-cause mortality (11.5 vs. 8.2%, p<0.001). P<0.001 Placebo Simvastatin LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RRR=Relative risk reduction Source: 4S Group. Lancet 1994;344:1383–1389 27

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 The CARE trial sought to evaluate the effect of statins in secondary prevention, particularly among those with average cholesterol levels. The mean total cholesterol level was <240 mg/dL and the LDL-C levels ranged between mg/dL. A total of 4,159 patients with a history of myocardial infarction were randomized to pravastatin (40 mg) or placebo for 5 years. Treatment with pravastatin resulted in a 24% relative risk reduction in the primary end point (myocardial infarction or coronary heart disease death). P=0.003 Placebo Pravastatin CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Srouce: Sacks FM et al. NEJM 1996;335:1001–1009 28

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 9 8.3 6.4 6 CHD Death (%) The LIPID study sought to evaluate the effect of statins in secondary prevention among those with a broad range of cholesterol levels. Patients with a history of known coronary artery disease were randomized to pravastatin (40 mg) or placebo over a mean of 6.1 years. Patients receiving pravastatin experienced a significant 24% relative risk reduction in coronary heart disease mortality, with no clinically significant adverse effects. 3 P<0.001 Placebo Pravastatin CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: LIPID Study Group. NEJM 1998;339:1349–1357 29

Heart Protection Study (HPS)
HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Heart Protection Study (HPS) Event Rate Ratio (95% CI) Baseline LDL-C (mg/dL) Statin (n = 10,269) Placebo (n = 10,267) <100 282 (16.4%) 358 (21.0%) 100–129 668 (18.9%) 871 (24.7%) 130 1083 (21.6%) 1356 (26.9%) All patients 2033 (19.8%) 2585 (25.2%) Statin Better Statin Worse 0.76 (0.72–0.81) P<0.0001 The Heart Protection Study sought to evaluate the effect of simvastatin on all cause mortality in high risk patients regardless of LDL-C levels. Treatment with simvastatin resulted in a 12% relative risk reduction in all-cause mortality and a 24% relative risk reduction in the first occurrence of any major vascular event. The benefit of simvastatin even extended to individuals with a baseline LDL-C level <100 mg/dL. 0.4 0.6 0.8 1.0 1.2 1.4 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 30

Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) 5,804 patients aged 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 Unlike many of the previous statin trials that excluded older individuals, the PROSPER trial sought to determine whether the benefit of statin therapy extended to a high risk elderly population. A total of 5,804 patients over the age of 70 years were randomized to pravastatin (40 mg) or placebo over three years. Treatment with pravastatin resulted in a significant, but modest decrease in the primary composite end point of coronary heart disease death, non-fatal MI and stroke. Importantly, there was no clear benefit for women in this trial. 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: 31

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 1 2 3 4 5 6 Atorvastatin (10 mg) 22% RRR 0.10 Major CV Event* (%) Atorvastatin (80 mg) 0.05 P<0.001 0.00 Following the Heart Protection Study, the TNT study sought to determine whether high dose statin therapy provided additional cardiovascular benefit among individuals with chronic coronary heart disease. All patients entered an open-label eight week period with low dose atorvastatin (10 mg). Those who experienced a statin related side effect or did not achieve an LDL-C level <130 mg/dL were excluded prior to randomization. High dose atorvastatin (80 mg) resulted in a significant 22% relative risk reduction in the primary composite endpoint (death from coronary heart disease, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke) as compared to low dose atorvastatin (10 mg). Paralleling the reduction in the composite primary endpoint was a decrease in the LDL-C levels to 77 mg/dL and 101 mg/dl in the high and low dose atorvastatin arms, respectively. There were no differences in overall mortality. These results add to the body of data obtained in the PROVE IT-TIMI 22 and HPS trials, demonstrating a benefit with lower LDL-C levels in individuals with coronary heart disease. 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: 32

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 Cumulative Hazard (%) Atorvastatin (80 mg) 4 HR=0.89, P=0.07 The IDEAL study evaluated the effect of intensive vs. moderate lipid lowering therapy in patients with a history of MI. Patients were randomized to receive atorvastatin (80 mg) or simvastatin (20 mg) over a mean period of 5 years. The primary endpoint was occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. There was no significant difference in the primary endpoint (HR 0.89, 95% CI, , p=0.07), despite an LDL-C difference of 23 mg/dL (81 mg/dL vs. 104 mg/dl in the atorvastatin vs. simvastatin treatment groups, respectively). There was, however, a significant reduction in nonfatal MI (6.0% vs. 7.2% respectively, p=0.02), major cardiovascular events, and any coronary event. There was no difference in mortality endpoints between the two groups. Importantly, the primary endpoint did not include stroke. When stroke was added to the primary end point, however, the relative risk reduction was similar to that seen in the TNT study. 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: 33

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 10 HPS TNT (atorvastatin 10 mg/d) 5 TNT (atorvastatin 80 mg/d) Data from the main secondary prevention trials (prior to publication of the IDEAL trial) are displayed here. The lowering of LDL-C levels with statin therapy leads to a reduction in cardiovascular morbidity and mortality, at multiple baseline risk levels. 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: 34

High-dose statin therapy does not provide CV benefit after a MI
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:

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 Relative Risk Reduction Absolute Number Needed To Treat Primary Secondary Major CHD events 29.2 20.8 1.66 2.4 60 33 Major CV events 14.4 17.8 0.37 0.8 268 125 Nonfatal MI 31.7 NA 1.65 61 PCI or CABG 33.8 20.3 1.08 2.7 93 37 This table compares the risk reduction seen in this meta-analysis of mainly primary prevention patients to the risk reduction seen in secondary prevention patients as determined by the meta-analysis by the Cholesterol Treatment Trialists’ Collaborators. While the relative risk reduction with statin therapy is similar in primary and secondary prevention patients, the absolute risk reduction is lower in primary prevention patients due to their lower rate of cardiovascular events overall. This translates into a higher number needed to treat to prevent one cardiovascular event. In this primary prevention analysis, 60 patients would need to be treated over the average trial follow-up of 4.3 years to prevent one major coronary event. *This does not included data from Jupiter. 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: 36

HMG-CoA Reductase Inhibitor Evidence: Effect of Intensive Therapy
Magnitude of event reduction among trials of intensive statin therapy RR in MI or CHD Death (%) RR in Primary End Point (%) LDL-C Reduction (mg/dL) Duration (years) Population Trial 11 23 5 Stable CAD (N = 8888) IDEAL 21 22 24 Stable CAD (N =10,001) TNT 15 14 2 ACS (N = 4497) A to Z 16 33 ACS (N = 4162) PROVE IT- TIMI 22 Four trials of aggressive statin therapy have shown that intensive LDL-C lowering in patients with an acute coronary syndrome or stable coronary artery disease improves outcomes. The degree of clinical benefit also seems to be related to the degree of LDL-C reduction. These trials support the notion that “lower is better”. It is important to note that the primary endpoints are not uniform across these trials. Specifically, the primary endpoints were: 1) PROVE IT-TIMI 22: A composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, and revascularization 2) A to Z: A composite of cardiovascular death, nonfatal myocardial infarction, readmission for an acute coronary syndrome, and stroke 3) TNT: A composite of death from coronary heart disease, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke 4) IDEAL: A composite of coronary death, confirmed nonfatal acute MI, and cardiac arrest with resuscitation Note: SI conversion factor: To convert LDL-C to mmol/L, multiply by 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: 37

HMG-CoA Reductase Inhibitor Evidence: Effect of Intensive Therapy
Cholesterol Treatment Trialists’ (CTT) Collaboration Meta-analysis of 169,138 patients randomized to at least 2 years of statin therapy 20 Control 21% relative risk reduction per mmol/L Statin 16% relative risk reduction per 0.5 mmol/L More statin 15 Five year risk of a major vascular event, % 10 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:

74,102 subjects in 35 randomized clinical trials with statins
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) The incidence of very high transaminases or myositis is relatively low with statin therapy. 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:

HMG-CoA Reductase Inhibitor: Adverse Effects
Risk factors for the development of myopathy* Concomitant Use of Meds Fibrate Nicotinic acid (Rarely) Cyclosporine Antifungal azoles** Macrolide antibiotics† HIV protease inhibitors Nefazadone Verapamil, Amiodarone Other Conditions Advanced age (especially >80 years) Women > Men especially at older age Small body frame, frailty Multisystem disease‡ Multiple medications Perioperative period Alcohol abuse Grapefruit juice (>1 quart/day) Certain medications and medical conditions can raise the effective blood level of statins, thus potentiating their risk 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: 40

Enterohepatic Circulation
Bile Acid Sequestrant: Mechanism of Action Gall Bladder  Cholesterol 7- hydroxylase Conversion of cholesterol to BA BA Secretion Bile Acid Enterohepatic Circulation Liver Terminal Ileum LDL Receptors VLDL and LDL removal Reabsorption of bile acids Bile acids are synthesized from cholesterol degradation. Bile acid resins bind bile acids in the intestine, thus interrupting enterohepatic circulation. When levels of bile acids decrease, there is an increase in hepatic synthesis of bile acids, thus reducing intrahepatic cholesterol. Standard doses of bile acid resins lower LDL-C levels by 15-25%. Importantly, this decrease in cholesterol activates HMG-CoA reductase, causing increased cholesterol synthesis and increased triglyceride concentrations. Adding a statin to a bile acid resin can block this HMG-CoA reductase activation. BA Excretion  LDL-C BA=Bile acid, LDL-C=Low density lipoprotein cholesterol, VLDL=Very low density lipoprotein 41

% Change from baseline at week 24
Bile Acid Sequestrant Evidence: Efficacy at Reducing LDL-C LDL-C HDL-C TG 15 10 10 5 5 † 3 % Change from baseline at week 24 -1 -5 -10 Placebo Colesevelam is a bile acid sequestrant that lowers levels of LDL-C and modestly raises levels of HDL-C. Through secondary activation of HMG-CoA reductase, colesevelam also modestly increases triglyceride levels. -15 Colesevelam 3.8 grams/day * -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: 42

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 The Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) randomized 3,806 men with primary hypercholesterolemia to cholestyramine (24 grams) or placebo for 7.4 years. Levels of LDL-C and total cholesterol were reduced by 20.3% and 13.4% in the cholestyramine arm, respectively, resulting in a 12.6% and 8.5% greater reduction than that seen in the placebo group. The risk of the primary end point (coronary heart disease death or nonfatal MI) was reduced by 19% in the cholestyramine group. This trial led to the concept that every 1% decrease in total cholesterol results in a 2% reduction in coronary events. P<0.05 Placebo Cholestyramine CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: The LRC-CPPT Investigators. JAMA 1984;251: 43

Ezetimibe: Mechanism of Action Production in liver
Absorption from intestine Dietary cholesterol Bloodstream LDL-C VLDL Biliary cholesterol Cholesterol synthesis Chylomicrons Ezetimibe inhibits the reabsorption of cholesterol in the proximal small intestine, resulting in less cholesterol returning to the liver via lymphatics. This results in the upregulation of LDL-C receptors on the surface of the liver. In general, ezetimibe results in a 15-25% reduction in LDL-C levels. While there are no clinical outcome trials with ezetimibe at the present time, such trials are in progress. Fecal sterols and neutral sterols 44

Mean % change from baseline to week 12
Ezetimibe Evidence: Efficacy at Reducing LDL-C 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 –1.6 –5 Mean % change from baseline to week 12 –5.7 –10 This slide presents data from a phase III clinical trial of 892 patients with primary hypercholesterolemia randomized to ezetimibe (10 mg) or placebo for 12 weeks. Ezetimibe reduced levels of LDL-cholesterol by 16.9%, compared with an increase of 0.4% with placebo (p<0.01). Ezetimibe also significantly (but modestly) increased levels of HDL-C and decreased levels of triglycerides as compared to placebo. No randomized trials powered for clinical outcomes have been published yet. A surrogate endpoint trial, ENHANCE, involved 720 patients with heterozygous familial hypercholesterolemia who were randomly assigned to treatment with simvastatin (80 mg daily) with or without ezetimibe (10 mg daily). Decreases in LDL-C were greater in patients treated with combination therapy (56 versus 39 percent) as were increases in HDL-C (10 versus 8 percent). Despite the large additional reduction in LDL-C with ezetimibe, there was no statistically significant difference in the primary outcome of change from baseline in carotid intima-media thickness ( versus mm, p=0.29) after 2 years. There is some controversy, however, in how the IMT was measured. There did not appear to be a difference between the two arms in the small number of cardiovascular events seen in the trial (10 versus 7 events). In the SEAS trial (a study evaluating ezetimibe in aortic stenosis), patients randomized to ezetimibe had an increased rate of reported cancers. An interim analysis of two other trials evaluating simvastatin and ezetimibe (IMPROVE-IT and SHARP) found no increased risk of incident cancer but a trend toward an increase in cancer deaths. Placebo Ezetimibe 10 mg –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: 45

Dietary Adjuncts Evidence: Efficacy at Reducing LDL-C
Therapy Dose (g/day) Effect Dietary soluble fiber 5-10 (psyllium)  LDL-C 10-15% Soy protein 20-30  LDL-C 5-7% Stanol esters 1.5-2  LDL-C 15-20% A healthy diet, that includes increased amounts of whole grains, fiber, fruits, vegetables, soy protein, and stanol esters, can significantly reduce levels of LDL-C. LDL-C=Low density lipoprotein cholesterol Sources: Kwiterovich Jr PO. Pediatrics 1995;96: Lichtenstein AH. Curr Atheroscler Rep 1999;1: Miettinen TA et al. Ann Med 2004;36: 46

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 This slide is based on data from the Framingham study and demonstrates the relationship between relative risk of coronary heart disease and HDL-C levels. For every 10 mg/dL increase in HDL-C, the relative risk of CHD is reduced by about 50%. This supports the concept that low levels of HDL-C remain a significant risk for coronary heart disease and a target of great interest. 25 45 65 HDL-C (mg/dL) CHD=Coronary heart disease, HDL-C=High-density lipoprotein cholesterol Source: Kannel WB. Am J Cardiol 1983;52:9B–12B 47

Nicotinic Acid: Mechanism of Action Hepatocyte Systemic Circulation
HDL Serum VLDL results in reduced lipolysis to LDL Serum LDL VLDL VLDL secretion Apo B Hepatocyte Systemic Circulation Mobilization of FFA TG synthesis LDL Apo B Nicotinic acid (niacin) inhibits free fatty acid transport from peripheral tissues to the liver. This reduces hepatic synthesis of VLDL and triglyercides. Niacin also inhibits hepatic uptake of apolipoprotein A-1, a major component of HDL-C, thus increasing HDL-C levels. 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, Available at 48

Mean change from Baseline
Nicotinic Acid Evidence: Effect on Lipid Parameters 30% -50 -40 -30 -20 -10 10 20 30 30% 26% HDL-C 22% 15% 10% –9% Mean change from Baseline –14% –5% –17% –21% –22% –11% LDL-C –28% This slide shows representative data with extended release niacin. Niacin is the most effective medication for increasing levels of HDL-C; however, it also lowers levels of LDL-C and triglycerides. –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: 49

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 (%) 60 Nicotinic Acid Nicotinic acid stopped 50 Placebo 40 P=0.0012 In the Coronary Drug Project, men with electrocardiographic evidence of previous MI were randomized to up to 3 grams per day of niacin or placebo. Six years following treatment, there was a modest, non-significant reduction in mortality among individuals receiving niacin. However, nine years after discontinuation of niacin, there was a modest, but statistically significant reduction in mortality among those previously treated with niacin. 2 4 6 8 10 12 14 16 Years of follow-up MI=Myocardial infarction Source: Canner PL et al. JACC 1986;8:1245–1255 50

HDL-Atherosclerosis Treatment Study (HATS)
Nicotinic Acid Evidence: Secondary Prevention HDL-Atherosclerosis Treatment Study (HATS) 160 men with CAD, low HDL-C, and normal LDL-C randomized to simvastatin (10-20 mg) + niacin (1000 mg bid), simvastatin (10-20 mg) + niacin (1000 mg bid) + antioxidants, antioxidants, or placebo for 3 years A statin plus niacin provides benefit to men with CAD and low HDL-C levels * ** ** The HDL Atherosclerosis Intervention Trial (HATS) was a 3-year randomized, double-blind study of 160 patients with coronary artery disease, low HDL-C levels, and normal LDL-C levels. Patients were randomly assigned to treatment with one of four therapies, including simvastatin (10-20 mg daily) + niacin (1000 mg twice daily), simvastatin (10-20 mg daily) + niacin (1000 mg twice daily) + antioxidants, antioxidants, or placebo. Clinical events (cardiovascular death, myocardial infarction, stroke, or revascularization) occurred in 3% of simvastatin + niacin patients, 14% of simvastatin + niacin + antioxidant patients, and 24% of placebo patients. In addition, coronary stenosis on angiography progressed by 3.9% with placebo and by 0.7% with simvastatin + niacin + antioxidants (P=0.004). In contrast, the average stenosis regressed by 0.4% with simvastatin + niacin alone (P<0.001). Placebo (n=34) Placebo + Vitamins (n=39) Niacin/Simvastatin (n=33) Niacin/Simvastatin + Vitamins (n=40) *Includes cardiovascular death, MI, stroke, or need for coronary revascularization **p<0.01, but low absolute event rates CAD=Coronary artery disease, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Brown BG et al. NEJM 2001;345: 51

Nicotinic Acid Evidence: Secondary Prevention
Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact of Global Health Outcomes (AIM-HIGH) Trial 3414 patients with established CV disease randomized to niacin (up to 2000 mg/day) or placebo on a background of statin therapy for a mean of 3 years* Niacin provides no benefit to those with CV disease and low HDL-C levels 16.4% 20 Combination Therapy 16.2% Monotherapy Primary outcome (%)** 10 HR 1.02, p=0.79 1 2 3 4 Time (years) *The study was stopped prematurely **Composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary/cerebral revascularization CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol Source: AIM-HIGH Investigators. NEJM 2011;365:

Major vascular events (%)
Nicotinic Acid Evidence: Secondary Prevention Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial 25,673 patients with established CV disease randomized to extended release niacin (up to 2000 mg/day) plus laropiprant (40 mg/day) or placebo on a background of statin therapy for a median of 3.9 years* Niacin provides no benefit to those with CV disease and low HDL-C levels 15.0% 15 14.5% Placebo Niacin/Laropiprant 10 Major vascular events (%) 5 HR 0.96, p=0.29 1 2 3 4 Years of follow-up *The study was stopped prematurely CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol Source: Armitage J et al. Presented at Late Breaking Clinical Trials Session, ACC13,

Free Cholesterol in Extrahepatic tissues
Cholesterol Ester Transfer Protein Evidence: Mechanism of Action Liver LDL-R Vessel Wall CE SR-B1 CETP FC LDL/VLDL CE Bile LCAT Free Cholesterol in Extrahepatic tissues FC Nicotinic acid (niacin) inhibits free fatty acid transport from peripheral tissues to the liver. This reduces hepatic synthesis of VLDL and triglyercides. Niacin also inhibits hepatic uptake of apolipoprotein A-1, a major component of HDL-C, thus increasing HDL-C levels. HDL Inhibition of CETP limits the transfer of cholesterol esters from HDL particles to triglyceride-rich lipoproteins and results in elevated HDL cholesterol levels along with larger and less dense LDL cholesterol particles CE=Cholesterol ester, CETP=Cholesterol ester transfer protein, FC=Free cholesterol HDL=High density lipoprotein, LCAT=Lecithin carnitine acyl transferase, LDL=Low density lipoprotein, VLDL=Very low density lipoprotein 54

Cholesterol Ester Transfer Protein Evidence: Secondary Prevention
Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial 15,067 patients at high CV risk randomized to torcetrapib (60 mg/day) plus atorvastatin versus atorvastation alone for a median of 1.5 years* The CETP inhibitor, torcetrapib, is associated with increased CV risk P=0.001 9 3 6.2 P=0.006 6 5.0 2 All-cause mortality (%) Primary end point** (%) 1.2 0.8 3 1 Atorvastatin Atorvastatin and Torcetrapib Atorvastatin Atorvastatin and Torcetrapib *The trial was stopped prematurely **Composite of death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina CETP=Cholesterol ester transfer protein, CV=Cardiovascular Source: Barter PJ et al. NEJM 2007;357:

Cholesterol Ester Transfer Protein Evidence: Secondary Prevention
Dal-OUTCOMES Trial 15,871 patients with a recent ACS randomized to dalcetrapib (600 mg/day) or placebo for a median of 2.6 years The CETP inhibitor, dalcetrapib, is associated with no CV benefit P=0.52 8.3 9 8.0 6 Primary end point** (%) 3 Placebo Dalcetrapib *The trial was stopped prematurely **Composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation ACS=Acute coronary syndrome, CETP=Cholesterol ester transfer protein, CV=Cardiovascular Source: Barter PJ et al. NEJM 2007;357:

An elevated triglyceride level is associated with increased CHD risk
CHD Risk According to Triglyceride Levels Meta-analysis of 29 prospective studies evaluating the risk of CHD relative to triglyceride level (top third vs. bottom third) An elevated triglyceride level is associated with increased CHD risk Higher triglyceride levels are associated with a greater risk of coronary heart disease in women than in men. They are also associated with the formation of small, dense LDL-C particles, which are more atherogenic. CHD=Coronary heart disease Source: Sarwar N et al. Circulation 2007;115: 57

Fibrate: Mechanism of Action Fibrate + TG LPL + VLDL Intestine IDL
LDL-R Fibric acid derivatives (fibrates) enhance lipoprotein lipase activity and hepatic bile secretion, leading to reduced hepatic triglyceride production. Fibrates up regulate both lipoprotein lipase and apolipoprotein CIII, thereby enhancing the catabolism of triglyceride-rich particles. In addition, fibrates activate peroxisome proliferator-activated receptors (PPARs), leading to an increase in HDL-C associated apolipoprotein AI and AII production. CE CE FC FC Liver Nascent HDL Macrophage Mature HDL CE=Cholesterol ester, FC=Free cholesterol, HDL=High density lipoprotein, IDL=Intermediate density lipoprotein, LDL-R=Low density lipoprotein receptor, LPL=Lipoprotein lipase, TG=Triglyceride, VLDL=Very low density lipoprotein 58

Effect on Lipid Parameters
Fibrate Evidence: Effect on Lipid Parameters 180 patients with type IIa or IIb hyperlipidemia randomized to fenofibrate (100 mg three times daily) or placebo for 24 weeks Type IIa hyperlipidemia Type IIb hyperlipidemia 50 40 30 20 +15* +11* 10 LDL TG LDL TG Mean % change from baseline HDL HDL -10 -6* -20 A total of 147 adults with type IV or V hyperlipoproteinemia were randomized to receive fenofibrate (100 mg) or placebo three times a day for eight weeks. Group A included 55 patients with triglyceride levels of mg/dL and group B included 92 patients with triglyceride levels of mg/dL. In both groups, fenofibrate significantly lowered levels of total cholesterol, VLDL, and triglycerides and increased levels of HDL-C. In group B, fenofibrate significantly increased the level of LDL-C. -20* -30 -40 -38* -45* -50 *p<0.01 HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride Source: Knopp RH et al. Am J Med 1987;83:50-9 59

% CHD Death/Nonfatal MI
Fibrate Evidence: Primary and Secondary Prevention 42% Treatment arm Placebo 22% 22 22*** 9% 17 15 % CHD Death/Nonfatal MI 13.6 66% 13 34% 8 4.1*** 2.7 2.7 Fibrate therapy significantly reduces coronary heart disease death and nonfatal MI among men in the primary prevention setting. Results in the secondary prevention setting are mixed. In the VA-HIT study, there was a significant reduction in coronary heart disease death and nonfatal MI. In the BIP study, this effect was only seen in the subgroup of patients with triglyceride levels 200 mg/dL. HHS HHS* Primary Prevention Secondary Prevention *Post hoc analysis of subgroup with TG >200 mg/dL and HDL-C <42 mg/dL **Post hoc analysis of subgroup with TG 200 mg/dL and HDL-C <35 mg/dL ***Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05) HDL-C=High density lipoprotein cholesterol, TG=Triglyceride Sources: Frick MH et al. NEJM 1987;317: Manninen V et al. Circulation 1992;85:37-45 BIP Study Group. Circulation 2000;102:21-27 Rubins HB et al. NEJM 1999;341: 60

Fibrate Evidence: Primary Prevention
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) 9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 years A fibrate does not provide significant additional benefit* in diabetics 11% RRR 9 5.9 6 5.2 CHD Death or Nonfatal MI (%) 3 P=0.16 The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study sought to assess the effect of fibrate therapy on cardiovascular disease events in patients with type 2 diabetes mellitus. A total of 9795 individuals with diabetes not on statin therapy at study entry were randomized to fenofibrate (200 mg daily) or placebo for 5 years. The primary outcome was a composite of coronary events, including coronary heart disease death or non-fatal myocardial infarction. There was no statistically significant reduction in the primary end point with fibrate therapy (5.2% vs. 5.9%, hazard ratio [HR] 0.89, 95% CI ; p=0.16). Treatment with fenofibrate, however, was associated with less albuminuria progression (p=0.002) and less retinopathy needing laser treatment (5.2% vs 3.6%, p=0.0003). Some of the disappointing results of the FIELD trial may have been due to a higher than expected use of statin therapy in the placebo group. Placebo Fenofibrate *Unadjusted for concomitant statin use CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Keech A et al. Lancet 2005;366: 61

Primary and Secondary Prevention
Fibrate Evidence: Primary and Secondary Prevention Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial 5,518 diabetic patients on statin therapy randomized to fenofibrate (160 mg) or placebo for 4.7 years On a background of statin therapy, a fibrate does not reduce CV events in diabetics 8% RRR 3 2.4 2.2 CV death, nonfatal stroke or nonfatal MI (%/year) 2 1 In the ACCORD trial, 5,518 diabetic patients already on statin therapy were randomized to fenofibrate or placebo and followed for 4.7 years. The addition of fenofibrate to statin therapy yielded no significant risk reduction of the primary endpoint (cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction). The mean triglyceride level in the overall study, however, was just 162 mg/dL. Among a pre-specified subgroup of dyslipidemic patients (high triglycerides, low HDL), a possible benefit was suggested. P=0.32 Placebo Fenofibrate CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: ACCORD study group. NEJM 2010;362:

Effect of Pharmacotherapy on Lipid Parameters
Good - 9% + 1% - 18% - 13% Ezetimibe % + 4-12% % % Statins* - 30% % - 4-21% - 19% Fibrates Reasonable to Poor % % % Nicotinic acid Poor Neutral or + 3% % - 7-10% Bile acid sequestrants Patient tolerability TG HDL-C LDL-C TC Therapy Lipid-modifying therapies include HMG CoA reductase inhibitors (statins), fibrates, bile acid sequestrants (resins), nicotinic acid (and its derivatives), and ezetimibe. Statins are highly effective at lowering LDL-cholesterol levels and have a good tolerability profile.1-3 Data presented in this slide does not include rosuvastatin. Bile acid sequestrants are potent cholesterol-modifying agents. Adverse events such as gastrointestinal bloating, nausea and constipation limit compliance to bile acid sequestrants.1,2 Nicotinic acid, a B vitamin, is effective at reducing both LDL cholesterol and triglyceride concentrations, and increasing HDL cholesterol levels. To be effective, it must be given in pharmacologic doses. The value of nicotinic acid has been limited by the incidence of adverse events, which include flushing, gastrointestinal distress, liver toxicity, hyperglycemia. and hyperuricemia.1,2 Fibrates are effective at lowering triglyceride levels and raising HDL-C levels. However, in a majority of patients they are only moderately successful in reducing LDL-cholesterol.1,2 Ezetimibe is the first of a novel class of selective cholesterol-absorption inhibitors. Ezetimibe may be useful in patients that are intolerant of other lipid-modifying therapies and in combination with a statin in patients that are intolerant of large doses of statins or need further reduction in LDL cholesterol despite the maximum dose of a statin.4 References: 1. Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391. 2. National Cholesterol Education Program. Circulation 1994;98(3):1333–1445. 3. Knopp RH. N Engl J Med 1999;341:498–511. 4. Gupta EK, Ito MK. Heart Dis 2002;4:399–409. *Daily dose of 40mg of each drug, excluding rosuvastatin HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglyceride 63

Omega-3 Fatty Acids Evidence: Effect on Lipid Parameters
27 patients with hypertriglyceridemia and low HDL-C treated with omega-3 fatty acid (4 grams/day) for 7 months Total Cholesterol Triglyceride -10 -20 % Reduction -21* -30 Omega 3 fatty acids are another strategy available to lower triglyceride levels. -40 -46* -50 *P<0.05 HDL-C=High-density lipoprotein cholesterol Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18: 64

Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS)
Omega-3 Fatty Acids Evidence: Primary and Secondary Prevention Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS) 18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a statin or a statin alone for 5 years Omega-3 fatty acids provide CV benefit, particularly in secondary prevention The JELIS trial randomized 18,645 hypercholesterolemic patients in Japan to receive either 1800 mg of EPA daily with a statin (EPA group; n=9326) vs. a statin alone (controls; n=9319). After a 5-year follow-up, the primary endpoint of any major coronary event was reduced from 3.5% in the statin alone group to 2.8% in the EPA + statin group (RRR 19% p=0.011). In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18%, but this finding was not significant (1.4% in the EPA group vs 1.7% in the control group; p=0.132). Years *Composite of cardiac death, myocardial infarction, angina, PCI, or CABG CV=Cardiovascular, EPA=Eicosapentaenoic acid Source: Yokoyama M et al. Lancet 2007;369: 65

Outcome Reduction with Initial Glargine Intervention (ORIGIN)
Omega-3 Fatty Acids Evidence: Primary and Secondary Prevention Outcome Reduction with Initial Glargine Intervention (ORIGIN) 12,536 patients with IFG, IGT, DM, established CV disease, or CV risk factors randomized in 2 x 2 trial design to omega 3 fatty acids (at least 900 mg/day), insulin glargine (with a target fasting blood glucose <95 mg/dL) or placebo for a median of 6.2 years Low dose omega-3 fatty acids do not provide CV benefit in at risk individuals 2% RRR 15 9.3 9.1 10 CV death (%) 5 P=0.72 Placebo Omega 3 fatty acids CV=Cardiovascular, DM=Diabetes mellitus, IFG=Impaired fasting glucose, IGT=Impaired glucose tolerance Source: ORIGIN Trial Investigators. NEJM 2012;367:

Omega-3 Fatty Acids Evidence: Secondary Prevention
Diet and Reinfarction Trial (DART) 2,033 men with a history of a MI randomized to a diet of reduced fat with an increased ratio of polyunsaturated to saturated fat, increased fatty fish intake*, or increased fiber intake for 2 years Omega-3 fatty acids reduce all cause mortality** in men after a MI Omega-3 Fatty Acids Placebo All cause mortality (%) In the Diet and Reinfarction Trial (DART), 2033 men with a history of MI received one of three dietary recommendations: (a) reduced fat and increased ratio of polyunsaturated to saturated fat, (b) increased fatty fish intake, or (c) increased fiber intake. The fish group was advised to eat at least 2 portions of fatty fish (300 grams total), corresponding to a weekly intake of about 2.5 grams of eicosapentaenoic acid (EPA). Those who could not tolerate this fish intake were advised to supplement it with fish oil capsules. Those advised to eat fatty fish had a 29% relative decrease in two year all-cause mortality compared with the other two groups. *Corresponds to 2.5 grams of EPA (PUFA) **p<0.05 EPA=Eicosapentaenoic acid, MI=Myocardial infarction Source: Burr ML et al. Lancet 1989;2:

Omega-3 fatty acids provide significant CV benefit after a MI
Omega-3 Fatty Acids Evidence: Secondary Prevention Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI-Prevenzione) 11,324 patients with a history of a MI randomized to omega-3 polyunsaturated fatty acids [PUFA] (1 gram), vitamin E (300 mg), both or none for 3.5 years Omega-3 fatty acids provide significant CV benefit after a MI Percent of patients P=0.048 P=0.053 P=0.023 P=0.008 stroke 2 4 6 8 10 12 14 16 Death, NF MI, NF stroke (2 way) CV death, and NF (4 way) Omega-3 PUFA Placebo The GISSI trial randomized 11,324 patients with a history of MI to n-3 polyunsaturated fatty acids (PUFA) (1 gram daily), vitamin E (300 mg daily), both, or none for 3.5 years. Patients treated with n-3 PUFA, but not vitamin E, had a significantly lowered risk of the primary end point (a composite of death, nonfatal MI, and stroke). Treatment with n-3 PUFA decreased the relative risk of one primary end point by 10% in a two-way analysis (p=0.048) and 15% in a four-way analysis (p=0.023). Of note, the dose of n-3 PUFA used in this study (1 gram daily) is the dose recommended for patients with coronary heart disease, but is lower than the dose approved for triglyceride lowering (2-4 gram daily). CV=Cardiovascular, MI=Myocardial infarction, NF=Non-fatal, PUFA=Polyunsaturated fatty acids Source: GISSI Investigators. Lancet 1999;354: 68

Rate of reinfarction, stroke, or death* (%)
Omega-3 Fatty Acids Evidence: Secondary Prevention OMEGA Trial 3,827 patients 3-14 days following a MI randomized to omega-3 fatty acids (460 mg EPA mg DHA) or placebo for 1 year Omega-3 fatty acids provide no benefit following a MI in those with high utilization of risk reducing therapies 12 10.4 8.8 8 Rate of reinfarction, stroke, or death* (%) 4 P=0.10 Placebo Fatty acids Omega-3 fatty acid supplementation does not seem to help in persons who are on aspirin, a statin, and antihypertensive therapy, at least in the short-term. *This is a secondary endpoint DHA=Docosahexaenoic acid, EPA=Eicosapentaenoic acid, MI=Myocardial infarction Source: Rauch B et al. Circulation 2010;122:

Risk Assessment for LDL-C Lowering
A risk assessment tool* is needed for individuals with >2 RFs 10 20 2 RFs 0-1 RFs 10-year CHD Risk CAD or Risk Equivalent** The Framingham risk score can be used to accurately estimate 10 year coronary heart disease risk in most patient populations. There are no published tables to look at 10-year CVD event rates. *Such as the Framingham Risk Score (FRS) **Includes DM, non-coronary atherosclerotic vascular disease, and >20% 10-year CHD risk by the FRS CAD=Coronary artery disease, CHD=Coronary heart disease, DM=Diabetes mellitus, RF=Risk factor Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285: 70

Framingham Risk Score On Line Calculator
Risk Stratification: Framingham Risk Score On Line Calculator Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Risk Assessment Tool.

Step 5: Smoking Status Points Step 2: Total Cholesterol Points
Risk Stratification: Framingham Risk Score for Men Step 1: Age Points Step 3: HDL-C Points Step 5: Smoking Status Points Years Points 20-34 -9 35-39 -4 40-44 45-49 3 50-54 6 55-59 8 60-64 10 65-69 11 70-74 12 75-79 13 HDL-C (mg/dl) Points >60 -1 50-59 40-49 1 <40 2 Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 Nonsmoker Smoker 8 5 3 1 Step 6: Sum of Points Age Total Cholesterol HDL-C Systolic Blood Pressure Smoking Status Point Total Step 4: SBP Points SBP (mm Hg) If untreated If treated <120 1 2 >160 3 Step 7: 10-year CHD Risk Point Total 10-year Risk <0 <1% 6 2% 13 12% 1% 7 3% 14 16% 1 8 4% 15 20% 2 9 5% 16 25% 3 10 6% >17 >30% 4 11 8% 5 12 10% Step 2: Total Cholesterol Points The Framingham risk score is calculated with the following information: gender, age, total cholesterol, HDL cholesterol, systolic blood pressure and smoking status. This predicts 10-year CHD event rates. TC (mg/dl) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 <160 4 3 2 1 7 5 9 6 >280 11 8 CHD=Coronary heart disease, HDL-C=High density lipoprotein cholesterol, SBP=Systolic blood pressure, TC=Total cholesterol Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at 72

Step 5: Smoking Status Points Step 2: Total Cholesterol Points
Risk Stratification: Framingham Risk Score for Women Step 1: Age Points Step 3: HDL-C Points Step 5: Smoking Status Points Years Points 20-34 -7 35-39 -3 40-44 45-49 3 50-54 6 55-59 8 60-64 10 65-69 12 70-74 14 75-79 16 HDL-C (mg/dl) Points >60 -1 50-59 40-49 1 <40 2 Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 Nonsmoker Smoker 9 7 4 2 1 Step 6: Sum of Points Age Total Cholesterol HDL-C Systolic Blood Pressure Smoking Status Point Total Step 4: SBP Points SBP (mmHg) If untreated If treated <120 1 3 2 4 5 >160 6 Step 7: 10-year CHD Risk Point Total 10-year Risk <9 <1% 15 3% 22 17% 9 1% 16 4% 23 22% 10 17 5% 24 27% 11 18 6% >25 >30% 12 19 8% 13 2% 20 11% 14 21 14% Step 2: Total Cholesterol Points The Framingham risk score is calculated with the following information: gender, age, total cholesterol, HDL cholesterol, systolic blood pressure and smoking status. This predicts 10-year CHD event rates. The predicted risk is much less for women than men with the same number of points. TC (mg/dl) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 <160 4 3 2 1 8 6 11 5 >280 13 10 7 CHD=Coronary heart disease, HDL-C=High density lipoprotein cholesterol, SBP=Systolic blood pressure, TC=Total cholesterol Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at 73

Reynolds Risk Score On Line Calculator
Risk Stratification: Reynolds Risk Score On Line Calculator In addition to information collected as part of the Framingham Risk Score, the Reynolds Risk Score includes a hs-CRP level and a family history of premature CV disease in predicting one’s risk of adverse CV events Source: Reynolds Risk Score calculator.

Cut-points for Drug Therapy
ATP III LDL-C Goals and Cut-points for Drug Therapy Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy High risk: CHD or CHD risk equivalents (10-year risk >20%) <100 mg/dL (optional goal: <70) 100 mg/dL >100 mg/dL (<100 mg/dL: consider drug options) Moderately high risk: 2+ risk factors* (10-year risk 10% to 20%) <130 mg/dL (optional goal: <100) 130 mg/dL >130 mg/dL ( mg/dL: consider drug options) Moderate risk: 2+ risk factors* (10 year risk <10%) <130 mg/dL >160 mg/dL Lower risk: 0-1 risk factor* <160 mg/dL 160 mg/dL >190 mg/dL ( mg/dL: LDL-C lowering drug optional) The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) provides comprehensive evidence based guidance on LDL-C management for clinicians. *Risk factors for CHD include: cigarette smoking, hypertension (blood pressure >140/90 mmHg or on antihypertensive medication, HDL-C <40 mg/dl (>60 mg/dl is a negative risk factor), family history of premature CHD, age >45 years in men or >55 years in women ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes Source: Grundy S et al. Circulation 2004;110: 75

ATP III Classification of Other Lipoprotein Levels
Total Cholesterol HDL-Cholesterol Level (mg/dl) Classification <200 Desirable Borderline High >240 High Level (mg/dl) Classification >40 Minimum goal* 40-50 Desired goal* >50 High Triglyceride Level (mg/dl) Classification <150 Normal Borderline High High >500 Very High The NCEP ATP III guidelines identify LDL cholesterol as the primary target for lipid intervention, but recognize total cholesterol, HDL cholesterol, and triglycerides as important factors. *These goals apply to men. For women, the minimum goal is >50 mg/dL HDL=High density lipoprotein Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285: 76

AHA Primary Prevention of CV Disease in DM Cholesterol Recommendations
In adult patients, lipid levels should be measured at least annually and more often if needed to achieve goals. In adults <40 years of age with low-risk lipid values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, and triglycerides <150 mg/dL), lipid assessments may be repeated every 2 years. Lifestyle modification deserves primary emphasis for all individuals. Patients should focus on the reduction of saturated fat and cholesterol intake, weight loss (if indicated), and increases in dietary fiber and physical activity. These lifestyle changes have been shown to improve the lipid profile. AHA=American Heart Association, CV=Cardiovascular, DM=Diabetes mellitus, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Buse JB et al. Circulation 2007;115:

AHA Primary Prevention of CV Disease in DM
Cholesterol Recommendations (Continued) Primary Prevention In those >40 years of age without overt CVD, but with >1 major CVD risk factor*, the primary goal is an LDL-C level <100 mg/dL. If LDL-C lowering drugs are used, a reduction of at least 30-40% in LDL-C levels should be obtained. If the baseline LDL-C level is <100 mg/dL, statin therapy should be initiated based on risk factor assessment and clinical judgment. In those <40 years of age without overt CVD, but at increased risk of CVD either by clinical judgment or by risk calculator, the LDL-C goal is <100 mg/dL, and LDL-C lowering drugs should be considered if lifestyle changes do not achieve the goal. *Includes cigarette smoking, hypertension [BP >140/90 mm Hg or use of antihypertensive medication], low HDL-C cholesterol [<40 mg/dL], and family history of premature CHD [CHD in male first-degree relative <55 years of age; CHD in female first-degree relative <65 years of age]. AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Buse JB et al. Circulation 2007;115:

AHA and ADA Primary Prevention of CV Disease
in DM Cholesterol Recommendations Primary Prevention The ADA and AHA suggest different approaches to the management of HDL-C and triglyceride-associated CVD risk. The AHA suggests that in patients with triglyceride levels of mg/dL, a non-HDL-C goal of <130 mg/dL is a secondary target. If triglycerides are >500 mg/dL, therapeutic options include a fibrate or niacin before LDL-C lowering therapy and treatment of LDL-C to goal after triglyceride-lowering therapy. A non HDL-C level <130 mg/dL should be achieved if possible The ADA suggests lowering triglycerides to <150 mg/dL and raising HDL-C to <40 mg/dL. In women an HDL-C goal 10 mg/dL higher (>50 mg/dL) should be considered. ADA=American Diabetes Association, AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Sources: Buse JB et al. Circulation 2007;115: American Diabetes Association. Diabetes Care 2010;33:S11-61

ADA Cholesterol Recommendations for Patients with Diabetes Mellitus
Primary Prevention In most adult patients, a fasting lipid profile should be measured at least annually. In adults with low-risk lipid values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, and triglycerides <150 mg/dL), lipid assessments may be repeated every 2 years. Lifestyle modification focusing on the reduction of saturated fat, trans fat, and cholesterol intake; increase of omega-3 fatty acids, viscous fiber, and plant stanols/sterols; weight loss (if indicated); and increased physical activity should be recommended to improve the lipid profile in patients with DM. ADA=American Diabetes Association, DM=Diabetes mellitus, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: American Diabetes Association. Diabetes Care 2010;33:S11-61

ADA Cholesterol Recommendations for Patients with Diabetes Mellitus (Continued) Primary and Secondary Prevention Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels for diabetic patients: With overt CV disease Without CV disease who are over the age of 40 years and have >1 other CV disease risk factors For patients at lower risk (without overt CV disease and <40 years of age), statin therapy should be considered in addition to lifestyle therapy if LDL-C remains >100 mg/dL or in those with multiple CV disease risk factors. ADA=American Diabetes Association, CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol Source: American Diabetes Association. Diabetes Care 2010;33:S11-61

ADA Cholesterol Recommendations for Patients with Diabetes Mellitus (Continued) Primary and Secondary Prevention In individuals without overt CV disease, the primary goal is an LDL-C <100 mg/dL (2.6 mmol/L). In individuals with overt CV disease, a lower LDL-C goal of <70 mg/dL (1.8 mmol/L), using a high dose of statin is an option. If drug-treated patients do not reach the above targets on maximal tolerated statin therapy, a reduction in LDL-C of approximately 30-40% from baseline is an alternative therapeutic goal. Triglyceride levels <150 mg/dL (1.7 mmol/L) and HDL-C >40 mg/dL (1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women, are desirable. However, LDL-C targeted statin therapy remains the preferred strategy. ADA=American Diabetes Association, CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: American Diabetes Association. Diabetes Care 2010;33:S11-61

ADA Cholesterol Recommendations for
Patients with Diabetes Mellitus (Continued) Primary Prevention Triglyceride levels <150 mg/dL (1.7 mmol/L) and HDL-C >40 mg/dL (1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women, are desirable. However, LDL-C targeted statin therapy remains the preferred strategy. If targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CV disease outcomes or safety. Statin therapy is contraindicated in pregnancy. ADA=American Diabetes Association, CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: American Diabetes Association. Diabetes Care 2010;33:S11-61

B Cholesterol Management Recommendations (Continued)
Secondary Prevention A lipid profile should be established in all patients, and for hospitalized patients, lipid-lowering therapy as recommended below should be initiated before discharge Lifestyle modifications including daily physical activity and weight management are strongly recommended for all patients Dietary therapy for all patients should include reduced intake of saturated fats (to <7% of total calories), trans fatty acids (to <1% of total calories), and cholesterol (to <200 mg/d) I IIa IIb III B Source: Smith SC Jr. et al. JACC 2011;58:

A C B Cholesterol Management Recommendations (Continued)
Secondary Prevention I IIa IIb III A In addition to therapeutic lifestyle changes, statin therapy should be prescribed in the absence of contraindications or documented adverse effects An adequate dose of statin should be used that reduces LDL-C to <100 mg/dL AND achieves at least a 30% lowering of LDL-C Patients who have triglycerides >200 mg/dL should be treated with statins to lower non–HDL-C to <130 mg/dL I IIa IIb III C I IIa IIb III B Source: Smith SC Jr. et al. JACC 2011;58:

C B B Cholesterol Management Recommendations (Continued)
Secondary Prevention I IIa IIb III C Patients who have triglycerides >500 mg/dL should be started on fibrate therapy in addition to statin therapy to prevent acute pancreatitis If treatment with a statin (including trials of higher-dose statins and higher-potency statins) does not achieve the goal selected for a patient, intensification of LDL-C–lowering drug therapy with a bile acid sequestrant or niacin is reasonable For patients who do not tolerate statins, LDL-C–lowering therapy with bile acid sequestrants and/or niacin is reasonable I IIa IIb III B I IIa IIb III B Source: Smith SC Jr. et al. JACC 2011;58:

C B C Cholesterol Management Recommendations (Continued)
Secondary Prevention I IIa IIb III C It is reasonable to treat very high-risk* patients with statin therapy to lower LDL-C to <70 mg/dL In patients who are at very high risk* and who have triglycerides >200 mg/dL, a non–HDL-C goal of < mg/dL is reasonable The use of ezetimibe may be considered for patients who do not tolerate or achieve target LDL-C with statins, bile acid sequestrants, and/or niacin I IIa IIb III B I IIa IIb III C *Presence of established CVD plus 1) multiple major risk factors (especially diabetes), 2) severe and poorly controlled risk factors (especially continued cigarette smoking), 3) multiple risk factors of the metabolic syndrome (especially high triglycerides >200 mg/dL plus non-HDL-C >130 mg/dL with low HDL-C <40 mg/dL, and 4) patients with an ACS ACS=Acute coronary syndrome, CVD=Cardiovascular disease, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Smith SC Jr. et al. JACC 2011;58:

B Cholesterol Management Recommendations (Continued)
Secondary Prevention For patients who continue to have an elevated non-HDL-C while on adequate statin therapy, consider niacin or fibrate therapy For all patients, it may be reasonable to recommend omega-3 fatty acids from fish or fish oil capsules (1 gram/day) for CV disease risk reduction I IIa IIb III B CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol Source: Smith SC Jr. et al. JACC 2011;58:

The Evidence for Current Cardiovascular Disease Prevention Guidelines:

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