1. Cholesterol, Cholesterol Therapies, and Cholesterol Guidelines
Andrew P. DeFilippis, Ty J. Gluckman, James Mudd, Catherine Campbell, Vera Bittner, Gregg Fonarow & Roger S. Blumenthal

2. Chylomicrons, VLDL, and their catabolic remnants
Lipoprotein Classes
Chylomicrons, VLDL, and their catabolic remnants
LDL
HDL
> 30 nm
20–22 nm
9–15 nm
Each major lipoprotein class impacts the development of atherosclerosis. The triglyceride-rich lipoproteins (chylomicrons, very low density lipoprotein (VLDL), and their catabolic remnants) and low-density lipoprotein (LDL) are potentially proinflammatory and know to be pro-atherosclerotic, whereas high-density lipoprotein (HDL) is potentially anti-inflammatory and anti-atherosclerotic.
References:
1. Doi H, Kugiyama K, Oka H, Sugiyama S, Ogata N, Koide SI, Nakamura SI, Yasue H. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation 2000;102:
2. Colome C, Martinez‑Gonzalez J, Vidal F, de Castellarnau C, Badimon L. Small oxidative changes in atherogenic LDL concentrations irreversibly regulate adhesiveness of human endothelial cells: effect of the lazaroid U74500A. Atherosclerosis 2000;149:
3. Cockerill GW, Rye K-A, Gamble JR, Vadas MA, Barter PJ. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol 1995;15:
Potentially
pro-inflammatory
Potentially
anti-inflammatory
Doi H et al. Circulation 2000;102:
Colome C et al. Atherosclerosis 2000;149:
Cockerill GW et al. Arterioscler Thromb Vasc Biol
1995;15:

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

4. CHD 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)
The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in Since the publication of ATP III, 5 major clinical end point-driven trials of statin therapy were published (prior to July 2004). These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy.
Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering treatment in high-risk patients and support the ATP III treatment goal of a low-density lipoprotein cholesterol (LDL-C) level <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to the ATP III treatment algorithm are listed below.
In high-risk individuals, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option. This option also extends to very high-risk individuals that have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk individual has high levels of triglycerides or low levels of high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-C lowering drug.
For moderately high-risk individuals (with 2+ risk factors and a 10-year risk of 10% to 20%), the recommended LDL-C goal is <130 mg/dL; however, an LDL-C goal <100 mg/dL is a therapeutic option. The latter option also extends to moderately high-risk individuals with a baseline LDL-C of 100 to 129 mg/dL.
When LDL-lowering drug therapy is employed in high-risk or moderately high-risk individuals, it is advised that the intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Any individual at high or moderately high risk that has lifestyle-related risk factors (e.g., obesity, physical inactivity, elevated triglycerides, low HDL-C, or the metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of the LDL-C level. Finally, for individuals in lower-risk categories, the goals and cut points of therapy remain unchanged.
LDL-Cholesterol (mg/dL)
CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol
Grundy S et al. Circulation 2004;110:227-39

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

6. 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
Statins inhibit the HMG-CoA Reductase enzyme which leads to a reduction in hepatic intracellular cholesterol.
Geranylgeranylated
proteins
Ubiquinones

7. 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 the upregulation of LDL receptors on the surface of hepatocytes. This increase in hepatocyte LDL receptors results in increased clearance of LDL cholesterol particles from the serum, ultimately lowering total serum LDL cholesterol levels.
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

8. HMG-CoA Reductase Inhibitor: Dose-Dependent Effect
The Rule of 6’s
The recommended starting dose of each statin drug results in a mean reduction in LDL-C of approximately 19% to 37%. Thereafter, each doubling of the dose results in a 6% (approximate) lowering of LDL-C. 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 the most potent (Rosuvastatin was not included in this study).
Each doubling of the statin dose produces an additional 6% (approximate) reduction in the LDL-C level
Illingworth DR. Med Clin North Am 2000;84:23-42

9. 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
Data presented as absolute reductions in LDL-C* (mg/dL) and percent reductions in LDL-C (in parentheses)
*Standardized to LDL-C 186 mg/dL (mean concentration in trials) before Rx.† Independent of pre-Rx LDL-C
‡Maximum dose of 80 mg/d administered as two 40-mg tablets
§Not FDA approved at 80 mg/d
This slide represents data from a meta-analysis of trials with statin therapy to define treatment and dose effects of available statins. In addition to the data presented in the slide, the analysis demonstrated that the average lowering of LDL cholesterol with statins is 1.8 mmol/l (69 mg/dL) which reduced the risk of ischemic heart disease events by 60% and stroke by 17%. With the exception of rosuvastatin all FDA approved statin medications have been shown to reduce clinical events, such trials are ongoing for rosuvastatin.
FDA=Food and Drug Administration, LDL-C=Low density lipoprotein cholesterol, Rx=Treatment
Law MR et al. BMJ 2003;326:

10. HMG-CoA Reductase Inhibitor Trials: Chronology
The early statin trials demonstrated that statin therapy benefited both primary and secondary prevention patients with hypercholesterolemia. Subsequent trials extended this finding to patients with a broad range of cholesterol levels. The MIRACL trial was the first to show the benefit of statins in an acute coronary syndrome. More recent trials have demonstrated that intensive LDL-C reduction improves outcomes in patients with acute coronary syndromes and chronic coronary heart disease.
Study Population:
Primary prevention
Acute coronary syndromes
Chronic Coronary heart disease

11. HMG-CoA Reductase Inhibitor: 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
Statins provide 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 enrolled men (45-65 years old) with moderate hypercholesterolemia (272 ± 23 mg/dL) and no history of myocardial infarction. Pravastatin resulted in a 31% relative risk reduction in the rate of coronary heart disease death or nonfatal myocardial infarction, with no adverse effect on the risk of death from non-cardiovascular causes.
Placebo
Pravastatin
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction
Shepherd J et al. NEJM 1995;333:

12. HMG-CoA Reductase Inhibitor: 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
Statins provide benefit in those with average LDL-C levels
37% RRR 6
5.5 4
Rate of MI, unstable angina, or SCD (%)
3.5 2
AFCAPS/TEXCAPS was a primary prevention trial that randomized 6605 men and women with average total cholesterol (221mg/dl) and LDL-C (150mg/dl) and below average HDL-C (36mg/dl) to lovastatin mg or placebo, along with dietary modifications. 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. Lovastatin reduced LDL-C levels by 25% and raised HDL-C levels by 6%.
P<0.001
Placebo
Lovastatin
MI=Myocardial infarction, RRR=Relative risk reduction, SCD=Sudden cardiac death
Downs JR et al. JAMA 1998;279:1615–1622

13. HMG-CoA Reductase Inhibitor: Primary Prevention
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
There is no significant difference between the two treatment arms, but 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 objective of ALLHAT-LLA (a sub study of the larger ALLHAT trial) was 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.
Baseline mean total cholesterol was 224 mg/dL, LDL-C was 146 mg/dL, HDL-C was 48 mg/dL, and triglyceride was 152 mg/dL This trial specifically sought inclusion of groups that were previously underrepresented in primary prevention trials (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) and the cholesterol reductions seen in the treatment arm (17% for total cholesterol and 28% for LDL-C) were similar to that noted in previous trials. Importantly, the placebo arm had an 8% decrease in total cholesterol and an 11% decrease in LDL-C which contrasts with previous trials, where little or no change in cholesterol levels occurred. The 9% total cholesterol differential between treatment and placebo arms was roughly half of that seen in previous primary prevention trials and may well have been related to the large cross-over among patients with coronary heart disease, the non blinded fashion of the study, and the widespread use of statins in the usual care arm.
Years
CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk
ALLHAT Collaborative Research Group. JAMA 2002;288:

14. HMG-CoA Reductase Inhibitor: 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
Statins provide 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
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
ACSCOT-LLA was a substudy of the ASCOT trial and sought to assess the benefits of cholesterol reduction in the primary prevention of coronary heart disease in hypertensive patients not deemed hypercholesterolemic (total non-fasting cholesterol <250mg/dl) by conventional means. All patients had to have at least three other cardiovascular risk factors making this a moderate to high risk population.
Patients were randomized to treatment with atorvastatin (10 mg) or placebo. 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, hazard ratio 0.64 [95% CI ], p= Importantly, differences were noted in the first year of treatment and the LDL-C levels attained were lower than current goals. There was no significant difference in death between the two arms.
Follow-up (yr)
CHD=Coronary heart disease, RR=Relative risk
*Post-treatment LDL-C level
Sever PS et al. Lancet. 2003;361:

15. HMG-CoA Reductase Inhibitor: Primary Prevention
Relationship between LDL-C Levels and Event Rates in Primary Prevention Statin Trials 10
Statin 8
Placebo
WOSCOPS
WOSCOPS 6
AFCAPS
CHD event rate (%)
AFCAPS 4
ASCOT 2
ASCOT
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, WOSCOPS= West of Scotland Coronary Prevention Study
O’Keefe JH Jr et al. JACC 2004;43:2142-6

16. HMG-CoA Reductase Inhibitor: 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 treatment significantly reduces event rates
17.4% 5 10 15
Atorvastatin
Placebo
14.8%
Combined cardiovascular event rate (%)*
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.
Schwartz GG et al. JAMA 2001;285:

17. HMG-CoA Reductase Inhibitor: 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 treatment significantly reduces event rates 30
Atorvastatin
Pravastatin
16% RRR 25 20
Recurrent MI, cardiac death, UA, revascularization, or stroke 15 10 5
P =0.005
PROVE IT-TIMI 22 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.
Follow-up (months)
ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, UA=Unstable angina
Cannon CP et al. NEJM 2004;350:

18. HMG-CoA Reductase Inhibitor: 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 treatment produces a trend towards reduced cardiovascular events
Placebo + Simvastatin 20 mg/day
Simvastatin 40/80 mg/day
Time from randomization (months)
Cumulative event rate (%)* 5 10 15 20 4 8 12 16 24
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.
*Includes CV death, MI, readmission for an ACS, and CVA
de Lemos JA et al. JAMA 2004;292:

19. HMG-CoA Reductase Inhibitor: 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
Statins provide significant benefit in those with average LDL-C levels
30% RRR
11.5 12
8.2 8
Mortality (%) 4
P<0.001
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).
Placebo
Simvastatin
MI=Myocardial infarction, RRR=Relative risk reduction
4S Group. Lancet 1994;344:1383–1389

20. HMG-CoA Reductase Inhibitor: 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
Statins provide 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
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).
Placebo
Pravastatin
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction
Sacks FM et al. NEJM 1996;335:1001–1009

21. HMG-CoA Reductase Inhibitor: 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
Statins provide significant benefit across a broad range of cholesterol levels
24% RRR 9
8.3
6.4 6
CHD Death (%) 3
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.
P<0.001
Placebo
Pravastatin
CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction
LIPID Study Group. NEJM 1998;339:1349–1357

22. HMG-CoA Reductase Inhibitor: Secondary Prevention
Heart Protection Study (HPS)
20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 years
Statins provide significant benefit across a broad range of LDL-C levels
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
CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus,
HPS Collaborative Group. Lancet 2002;360:7-22

23. HMG-CoA Reductase Inhibitor: Secondary Prevention
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
Statins provide benefit in older men 20
Placebo
Pravastatin
CHD death, non-fatal MI, stroke (%) 10
15% RRR, P=0.014
Unlike many of the previous statin trials that excluded older individuals, PROSPER 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, MI=Myocardial infarction, RRR=Relative risk reduction
Shepherd J et al. Lancet 2002;360:

24. HMG-CoA Reductase Inhibitor: Secondary Prevention
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 statins provide benefit in chronic CHD
0.15 1 2 3 4 5 6
Atorvastatin (10 mg)
Atorvastatin (80 mg)
22% RRR
0.10
Major CV Event* (%)
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
CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction
*Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke
LaRosa JC et al. NEJM 2005;352:

25. HMG-CoA Reductase Inhibitor: 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 statins provide a strong trend towards benefit after a MI
Simvastatin (20 mg)
Atorvastatin (80 mg) 12 8
Cumulative Hazard (%) 4
HR=0.89, P=0.07
The Incremental Decrease in End Points Through Aggressive Lipid Lowering (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
HR=Hazard ratio, MI=Myocardial infarction
*Includes coronary death, hospitalization for nonfatal acute MI, or cardiac arrest with resuscitation
Pedersen et al. JAMA 2005;294:

26. HMG-CoA Reductase Inhibitor: 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
LIPID
Event (%) 15
LIPID
CARE
CARE 10
HPS
HPS
TNT (atorvastatin 10 mg/d) 5
TNT (atorvastatin 80 mg/d)
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, HPS=Heart Protection Study, LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study, TNT=Treating to New Targets
LDL-C=Low density lipoprotein cholesterol
LaRosa JC et al. NEJM 2005;352:

27. HMG-CoA Reductase Inhibitor: Intensive 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 an intensive strategy in patients with an acute coronary syndrome or stable coronary artery disease improves outcomes. In addition, the degree of LDL-C reduction seems to be related to the degree of clinical benefit.
These trials support the idea that “lower is better”, whereby aggressive lowering of LDL-C is a primary means of reducing morbidity and mortality in patients with (or at risk for) cardiovascular disease. These trials also support the notion that increasing statin dose (intensity) reduce cardiovascular risk.
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
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
Cannon CP et al. JAMA 2005;294:

28. 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.
Kashani A et al. Circulation 2006;114:

29. 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
Pasternak RC et al. Circulation 2002;106:

30. Bile Acid Sequestrant: Mechanism of Action Enterohepatic Circulation
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 their 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 cholesterol

31. Bile Acid Sequestrant: Efficacy at Reducing LDL-C
HDL-C TG †
% Change from baseline at week 24
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. *
Placebo
Colesevelam 3.8 grams/day
*P<0.001 vs placebo
†P=0.04 vs placebo
Insull W et al. Mayo Clin Proc 2001;76:971-82

32. Bile Acid Sequestrant: 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
Bile acid sequestrants provide 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
The LRC-CPPT Investigators. JAMA 1984;251:351-64

33. Ezetimibe: Mechanism of Action
Production in liver
Absorption from intestine
Bloodstream
Dietary cholesterol
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

34. Ezetimibe: Efficacy at Reducing LDL-C
Pooled Phase III Study Results
LDL-C
HDL-C
Triglycerides* +5 +1
+1.0 –2 –5
Mean % change from baseline to week 12 –8
–10
–15
This slide presents pooled data from two studies of ezetimibe that enrolled 1,719 patients with primary hypercholesterolemia. Patients were randomized to ezetimibe (10 mg) or placebo for 12 weeks. Ezetimibe reduced levels of LDL-cholesterol by 18%, compared with an increase of 1% with placebo (p<0.01). Ezetimibe also significantly (but modestly) increased levels of HDL-C and decreased levels of triglycerides as compared to placebo.
Placebo
Ezetimibe 10 mg
–18
–20
*Median % change
Knopp RH. Int J Clin Pract 2003;57:363-8

35. Dietary Adjuncts: Efficacy at Reducing LDL-C
Therapy
Dose (g/day)
Effect
Dietary soluble fiber
2-8
 LDL-C 5-10%
Soy protein
20-30
 LDL-C 5-7%
Stanol esters
1.5-4
 LDL-C 10-15%
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.
Jones PJ. Curr Atheroscler Rep 1999;1:
Lichtenstein AH. Curr Atheroscler Rep 1999;1:
Rambjor GS et al. Lipids 1996;31:S45-S49
Ripsin CM et al. JAMA 1992;267:

36. Diet Evidence: Effect on Lipid Parameters and CRP
46 dyslipidemic patients randomized to a low fat diet, a low fat diet and lovastatin (20 mg), or a dietary portfolio* for 4 weeks
A diversified diet improves lipid parameters and CRP levels 30
LDL-C
LDL-C:HDL-C
CRP 20 10
Low fat diet
Statin
Change from Baseline (%)
-10
Dietary portfolio*
-20
-30
-40
This trial randomized 46 healthy hyperlipidemic adults to one of three interventions for one month: (a) a low-fat diet, (b) a low-fat diet plus lovastatin (20 mg daily), or (c) a dietary portfolio high in almonds, plant sterols, soy protein, and viscous fibers.
The low-fat diet, low-fat diet + statin, and dietary portfolio groups had mean reductions in C-reactive protein of 10.0% (p=0.27), 33.3% (p=0.002) and 28.2% (p=0.02), respectively. The reductions in levels of LDL-C were 8.0% (p=0.002), 30.9% (p<0.001) and 28.6% (p<0.001), respectively. CRP and LDL-C levels were significantly reduced in the dietary portfolio and low-fat diet + statin groups as compared to the low-fat diet alone group. There were no significant reductions in CRP and LDL-C levels in the low-fat diet + statin group as compared to the dietary portfolio group.
-50 2 4 2 4 2 4
Weeks
Weeks
Weeks
*Enriched in plant sterols, soy protein, viscous fiber, and almonds
Jenkins DJ et al. JAMA 2003;290:502-10

37. Nicotinic Acid: Mechanism of Action
Mobilization of FFA
Apo B
Serum VLDL results in reduced lipolysis to LDL
VLDL
VLDL
TG synthesis
VLDL secretion
Serum LDL
LDL
HDL
Liver
Circulation
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.
Hepatocyte
Systemic Circulation
Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in reduced LDL-C levels and increased HDL-C levels
FFA=Free fatty acids, HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride, VLDL=Very low density lipoprotein

38. Nicotinic Acid: Efficacy at Raising HDL-C
30%
30%
HDL-C
26%
22%
15%
10%
–9%
Change from Baseline
–14%
–5%
–17%
–21%
–22%
LDL-C
–11%
–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 LDL-C and triglycerides.
–35% TG
–39%
–44%
Dose (mg)
500
1000
1500
2000
2500
3000
Goldberg A et al. Am J Cardiol 2000;85:

39. Nicotinic Acid: Secondary Prevention
Coronary Drug Project (CDP)
8,341 men with previous myocardial infarction randomized to nicotinic acid (3 grams) or placebo for 15 years
Nicotinic acid provides long-term benefit following a MI
100 90
Nicotinic Acid
Placebo 80 70
Survival (%) 60
Nicotinic acid stopped 50 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 is 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
Canner PL et al. JACC 1986;8:1245–1255

40. Nicotinic Acid: 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
Simvastatin + niacin benefits men with CAD and low HDL-C *
The HDL Atherosclerosis Intervention Trial (HATS) was a 3-year randomized double-blind study of 160 coronary artery disease patients with low HDL and normal LDL cholesterol 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. Furthermore, the average 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).
*Includes cardiovascular death, MI, stroke, or need for coronary revascularization
Brown BG et al. NEJM 2001;345:

41. CHD Risk According to Triglyceride Levels
Framingham Study
3.0
Men
2.5
Women
2.0 RR
1.5
1.0
0.5
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.
0.0 50
100
150
200
250
300
350
400
Triglyceride Level (mg/dL)
CHD=Coronary heart disease, RR=Relative Risk
Castelli WP. Can J Cardiol 1988;4:5A-10A

42. Fibrate: Mechanism of Action+ TG
LPL +
VLDL
Intestine
IDL
LDL-R CE
Fibric acid derivatives (fibrates) enhance lipoprotein lipase activity and hepatic bile secretion and reduce 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 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,

43. Fibrate: Efficacy at Reducing Triglyceride
147 patients with type IV/V hyperlipoproteinemia randomized to fenofibrate (100 mg three times daily) or placebo for 8 weeks
TG = 350–499 mg/dL
TG = 500–1500 mg/dL 50 45 40 30 23 20 20 15 10 TG TG
Mean % change from baseline
LDL
HDL
LDL
HDL
-10
-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.
-30
-40
-50
-46
-60
-55
TG=Triglyceride level
Goldberg AC et al. Clin Ther 1989;11:69–83

44. Fibrate: Primary and Secondary Prevention
42% Rx
Placebo
22% 22
22*** 9% 17 15
13.6
% CHD Death/Nonfatal MI
66% 13
34% 8
4.1***
2.7
2.7
HHS
HHS*
BIP
BIP**
VA-HIT
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.
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)
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:

45. Fibrate: Secondary Prevention
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)
9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 yrs
Fenofibrate fails to provide significant additional benefit*
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 (not on statin therapy at study entry) with diabetes 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 statisically 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 statins in the placebo group.
Placebo
Fenofibrate
CHD=Coronary heart disease, MI=Myocardial infarction
*Unadjusted for concomitant statin use
Keech A et al. Lancet 2005;366:

46. Cholesterol Management Pharmacotherapy
Good
¯ 9%
­ 1%
¯ 18%
¯ 13%
Ezetimibe
¯ 14-29%
­ 4-12%
¯ 25-50%
¯ 19-37%
Statins*
¯ 30%
­ 11-13%
¯ 4-21%
¯ 19%
Fibrates
Reasonable to Poor
¯ 30-70%
­ 14-35%
¯ 10-20%
Nicotinic acid
Poor
Neutral or ­
­ 3%
¯ 10-18%
¯ 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.
Statins are highly effective in lowering LDL-cholesterol 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, skin problems, gastrointestinal distress, liver toxicity, hyperglycemia and hyperuricemia.1,2
Fibrates are effective triglyceride-lowering and HDL-C raising drugs. 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 maximum doses 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.
HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglycerides
*Daily dose of 40mg of each drug, excluding rosuvastatin

47. w-3 Fatty Acids: Efficacy at Reducing Triglyceride
27 patients with hypertriglyceridemia and low HDL-C treated with n-3 fatty acid (4 grams/day) for 7 months
Total Cholesterol
Triglyceride
-10
-20
% Reduction
-21*
-30
-40
Omega 3 fatty acids are another strategy available to lower triglyceride levels.
-46*
-50
*P<0.05
Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:

48. w-3 Fatty Acids: Primary and Secondary Prevention
JELIS Trial
18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a statin or a statin alone for 5 years
EPA provides additional cardiovascular benefit to those on statin therapy, particularly in secondary prevention
The JELIS trial randomized 18,645 hypercholesterolemic patients in Japan to receive either 1800 mg of EPA daily with statin (EPA group; n=9326) or statin only (controls; n=9319). After 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).
Composite of cardiac death, myocardial infarction, angina, PCI, or CABG
Yokoyama M et al. Lancet. 2007;369:1090-8

49. w-3 Fatty Acids: Secondary Prevention
Diet and Reinfarction Trial (DART)
Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI)
N-3 Fatty Acids
Placebo
All cause mortality (%)
Omega 3 fatty acid supplementation appears to lower CV events in several large clinical trials.
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.
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. n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary end point (a composite of death, nonfatal MI, and stroke). n-3 PUFA decreased the relative risk of the primary end point by 15% in 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).
DART* (n=3,482)
GISSI* (n=11,324)
w-3 fatty acids reduce mortality post MI
*Post myocardial infarction
Burr ML et al. Lancet 1989;2:
GISSI Investigators. Lancet 1999;354:

50. CHD Risk According to HDL-C Levels
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 level. 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
Kannel WB. Am J Cardiol 1983;52:9B–12B

51. Risk Profile 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 calculation can be used to accuratly estimate 10 year coronary heart disease risk in most patient populations.
CAD=Coronary artery disease, CHD=Coronary heart disease, DM=Diabetes mellitus, RF=Risk factor
*Such as the Framingham Risk Score (FRS)
**Includes DM, non-coronary atherosclerotic vascular disease, and >20% 10-year CHD risk by the FRS
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:

52. Framingham Risk Score: Men
Step 1: Age Points
Step 5: Smoking Status Points
Step 4: SBP 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
Age 20-39
Age 40-49
Age 50-59
Age 60-69
Age 70-79
Nonsmoker
Smoker 8 5 3 1
SBP (mmHg)
If untreated
If treated
<120 1 2
>160 3
Step 6: Sum of Points
Age
Total Cholesterol
HDL-C
Systolic Blood Pressure
Smoking Status
Point Total
Step 2: Total Cholesterol Points
Step 7: 10-year CHD Risk
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
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%
Framigham risk score is calculated with the following information: gender, age, total cholesterol, HDL cholesterol, systolic blood pressure and smoking status.
Step 3: HDL-C Points
HDL-C (mg/dl)
Points
>60 -1
50-59
40-49 1
<40 2

53. Framingham Risk Score: Women
Step 1: Age Points
Step 4: SBP 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
SBP (mmHg)
If untreated
If treated
<120 1 3 2 4 5
>160 6
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 2: Total Cholesterol Points
Step 7: 10-year CHD Risk
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
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%
Framigham risk score is calculated with the following information: gender, age, total cholesterol, HDL cholesterol, systolic blood pressure and smoking status.
Step 3: HDL-C Points
HDL-C (mg/dl)
Points
>60 -1
50-59
40-49 1
<40 2

54. 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-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 guidelines.
*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
Grundy S et al. Circulation 2004;110:227-39

55. 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
Desirable
40-50
Borderline High
>50
High
Triglyceride
Level (mg/dl)
Classification
<150
Normal
Borderline High
High
>500
Very High
NCEP ATPIII identifies LDL cholesterol as the primary target for lipid intervention but recognizes total cholesterol, HDL cholesterol and triglycerides as important factors.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:

56. Cholesterol Management Guidelines (Continued)
Goals Recommendations
As set forth by the NCEP
Obtain a fasting lipid profile in all patients. For those with an MI, a fasting lipid profile should be obtained within 24 hours of admission.
Start therapeutic lifestyle changes in all patients, including:
Reduced intake of saturated fat (<7% of total calories) and cholesterol (<200 mg/day)
Addition of plant stanols/sterols (2 g/day) and viscous fiber (10-25 g/day) to enhance LDL-C lowering
Weight reduction
Increased physical activity
LDL-C=Low density lipoprotein cholesterol, NCEP=National Cholesterol Education Program
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:

57. Cholesterol Management Guidelines (Continued)
Goals Recommendations
As set forth by the NCEP
HMG-CoA reductase inhibitors (statins) are used first-line to achieve the LDL-C goal
If the LDL-C level is above goal, statin therapy should be intensified + the addition of a second LDL-C lowering agent
If the TG level is >150 mg/dl or the HDL-C level is <40 mg/dl, weight loss, physical activity, and smoking cessation should be emphasized
If the TG level is mg/dl after initiation of LDL-C lowering therapy, nicotinic acid or a fibrate should be considered
If the TG level is >500 mg/dl, nicotinic acid or a fibrate should be considered before starting LDL-C lowering therapy
HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, NCEP=National Cholesterol Education Program, TG=Triglyceride
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:

58. Cholesterol Management Guidelines
Secondary Prevention
Restriction of saturated fat (<7% of total calories), trans-fatty acids, and cholesterol (<200 mg/day) in all patients
Promotion of daily physical activity and weight management in all patients
Increase in w-3 fatty acid consumption in all patients
ACC/AHA secondary prevention guidelines for the restriction of saturated fat, trans-fatty acids and cholesterol is a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation. Daily physical activity and weight management is also a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation. Increase in omega-3 fatty acid consumption is a Level B, Class IIb (conflicting evidence based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) reccomendation.

59. Cholesterol Management Guidelines (Continued)
Secondary Prevention
Initiation or intensification of LDL-C lowering drug therapy in those with a baseline or on-treatment LDL-C level >100 mg/dl
Intensification of LDL-C lowering drug therapy to achieve a LDL-C <70 mg/dl
Initiation of LDL-C lowering drug therapy in those with a baseline LDL-C level of mg/dl to achieve a LDL-C level <70 mg/dl I
IIa
IIb
III I
IIa
IIb
III B
ACC/AHA secondary prevention guidelines for initiation or intensification of drug therapy for patients with an LDL >100mg/dl is a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation. Intensification of drug therapy to reduce LDL <70mg/dl is a Level A, Class IIa (level of certainty based on multiple RCT trial or meta-analysis suggests benefit is greater than risk) recommendation. Initiation of drug therapy to reduce LDL <70mg/dl is a Level B, Class IIa (certainty based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) recommendation.
LDL-C=Low density lipoprotein cholesterol

60. Cholesterol Management Guidelines (Continued)
Secondary Prevention
Intensification of LDL-C lowering drug therapy (Class I, Level B) or addition of a fibrate or niacin (Class I, Level B in men; Class I, Level C in women) in those with a TG level of mg/dl
Initiation of a fibrate or niacin before LDL-C lowering drug therapy in those with a TG level >500 mg/dl
Intensification of LDL lowering therapy in secondary prevention patients with a triglyceride level of mg/dl is a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation; the addition of a fibrate or niacin is a Level B, Class I in men and a Level C, Class I (generally agreed that benefit outweighs harm but only based on expert opinion or case series) recommendation in women. Initiation of a fibrate or niacin before LDL lowering therapy in patients with triglycerides >500mg/dl is a Level C, Class I (generally agreed that benefit outweighs harm but only based on expert opinion or case series) recommendation.
LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride

61. Cholesterol Management Guidelines (Continued)
Secondary Prevention
Reduction of non-HDL-cholesterol to <130 mg/dl in those with a TG level of mg/dl
Reduction of non-HDL-cholesterol to <100 mg/dl in those with a TG level of mg/dl I
IIa
IIb
III B
The reduction of non-HDL cholesterol to <130mg/dl in secondary prevention patients with a triglyceride level of mg/dl is a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation; reduction of non-HDL cholesterol to <100mg/dl is a Level B, Class IIa (certainty based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) recommendation.
HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride

62. Cholesterol Management Guidelines (Continued)
Secondary Prevention
Therapeutic options to reduce non-HDL-cholesterol include:
Intensification of LDL-C lowering drug therapy
Niacin (after initiation of LDL-C lowering drug therapy)
Fibrate therapy (after initiation of LDL-C lowering drug therapy) I
IIa
IIb
III B I
IIa
IIb
III B
Intensification of LDL-C lowering drug therapy in secondary prevention pateints with an elevated non-HDL cholesterol is a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation. The addition of niacin or fibrate therapy after initiation of LDL lowering therapy is a Level B, Class IIa (certainty based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) recommendation.
HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol