The Evidence for Current
Cardiovascular Disease
Prevention Guidelines:
Cholesterol Management
American College of Cardiolo...
Classification of
Recommendations and Levels of
Evidence

*Data available from clinical trials or
registries about the
use...
Icons Representing the Classification and
Evidence Levels for Recommendations
I IIa IIb III

I IIa IIb III

I IIa IIb III
...
Evidence for Current Cardiovascular Disease
Prevention Guidelines

Cholesterol, Cholesterol Therapies,
and Cholesterol Gui...
Lipoprotein Classes

Chylomicrons,
VLDL, and
their catabolic remnants

LDL

HDL

> 30 nm

20–22 nm

9–15 nm

Potentially
p...
Role of Lipoproteins in Atherogenesis
High plasma
LDL

HDL

LDL infiltration
into intima

Adherence
of platelets

( -)

En...
Attributable Risk Factors
for a First Myocardial Infarction
INTERHEART Study
100

90

PAR (%)

80
60
40

50
36

20
0

33
1...
Change in Total Cholesterol Levels
in the United States Over Time
National Health and Nutrition Examination Survey (NHANES...
Coronary Heart Disease Risk
According to LDL-C Level

Relative Risk for Coronary
Heart Disease (Log Scale)

3.7
2.9
2.2
1....
Therapies to Lower Levels of LDL-C
Class
3-Hydroxy-3-Methylglutaryl Coenzyme A (HMGCoA) reductase inhibitors [Statins]

Bi...
HMG-CoA Reductase Inhibitor:
Mechanism of Action
Inhibition of the cholesterol biosynthetic pathway
Squalene
synthase

HMG...
HMG-CoA Reductase Inhibitor:
Mechanism of Action
VLDL

Cholesterol
synthesis
LDL receptor
(B–E receptor)
synthesis
Intrace...
HMG-CoA Reductase Inhibitor:
Dose-Dependent Effect
The Rule of 6’s
Lovastatin 20/80*

28

Pravastatin 20/40*

12

27

6
35...
HMG-CoA Reductase Inhibitor:
Reduction in LDL-C
A meta-analysis of 164 trials*†‡
Statin

10 mg/d

20 mg/d

40 mg/d

80 mg/...
HMG-CoA Reductase Inhibitor:
Chronological Order of Event Driven
Trials
Study populations:
Primary prevention
Acute corona...
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
West of Scotland Coronary Prevention Study (WOSCOPS)
6,595 men wi...
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
West of Scotland Coronary Prevention Study (WOSCOPS)
Long-term fo...
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Air Force/Texas Coronary Atherosclerosis Prevention Study
(AFCAPS...
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
At...
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering
Arm (ASC...
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Relationship between LDL-C levels and event rates in select prima...
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Management of Elevated Cholesterol in the Primary
Prevention Grou...
HMG-CoA Reductase Inhibitor Evidence:
Primary Prevention
Justification for the Use of Statins in Prevention: An
Interventi...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Myocardial Ischemia Reduction with Aggressive Cholesterol
Lower...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Pravastatin or Atorvastatin Evaluation and Infection Therapy
(P...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Aggrastat to Zocor (A to Z) Trial
4,162 patients with an ACS ra...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Scandinavian Simvastatin Survival Study (4S)
4,444 patients wit...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Cholesterol and Recurrent Events (CARE) Study
4,159 patients wi...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Long-term Intervention with Pravastatin in Ischemic Disease
(LI...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Heart Protection Study (HPS)
Event Rate Ratio (95% CI)
Baseline...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Prospective Study of Pravastatin in the Elderly at Risk (PROSPE...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Treating to New Targets (TNT) Trial
10,001 patients with stable...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Incremental Decrease in End Points Through Aggressive Lipid
Low...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Relationship between LDL-C levels and event rates in secondary ...
HMG-CoA Reductase Inhibitor Evidence:
Secondary Prevention
Study of the Effectiveness of Additional Reductions in
Choleste...
HMG-CoA Reductase Inhibitor Evidence:
Degree of Benefit in Prevention Types
Meta-analysis of randomized controlled trials ...
HMG-CoA Reductase Inhibitor Evidence:
Effect of Intensive Therapy
Magnitude of event reduction among trials of intensive s...
HMG-CoA Reductase Inhibitor Evidence:
Effect of Intensive Therapy
Cholesterol Treatment Trialists’ (CTT) Collaboration
Met...
HMG-CoA Reductase Inhibitor:
Adverse Effects
74,102 subjects in 35 randomized clinical trials with statins
• 1.4% incidenc...
HMG-CoA Reductase Inhibitor:
Adverse Effects
Risk factors for the development of myopathy*
Concomitant Use of Meds

Other ...
Bile Acid Sequestrant:
Mechanism of Action

Gall Bladder

↑ Cholesterol 7-α hydroxylase
↑ Conversion of cholesterol to BA
...
Bile Acid Sequestrant Evidence:
Efficacy at Reducing LDL-C
15

LDL-C

HDL-C

TG
10

% Change from baseline
at week 24

10
...
Bile Acid Sequestrant Evidence:
Primary Prevention
Lipid Research Clinics-Coronary Primary Prevention Trial
(LRC-CPPT)
3,8...
Ezetimibe:
Mechanism of Action
Production in liver

Absorption from intestine

Bloodstream

Dietary cholesterol

LDL-C

Ch...
Ezetimibe Evidence:
Efficacy at Reducing LDL-C
892 patients with primary hypercholesterolemia randomized to ezetimibe
(10 ...
Dietary Adjuncts Evidence:
Efficacy at Reducing LDL-C
Therapy

Dose (g/day)

Effect

Dietary soluble fiber

5-10 (psyllium...
CHD Risk According to HDL-C Level
Framingham Study

CHD risk ratio

4.0

4.0

3.0
2.0

2.0
1.0

1.0
0
65
25
45
HDL-C (mg/d...
Nicotinic Acid:
Mechanism of Action
Mobilization of FFA
Apo B
VLDL
TG
synthesis

Hepatocyte

Apo B
VLDL

VLDL
secretion

S...
Nicotinic Acid Evidence:
Effect on Lipid Parameters
30%

Mean change from Baseline

30
15%

20
10

22%

26%

30%
HDL-C

10...
Nicotinic Acid Evidence:
Secondary Prevention
Coronary Drug Project (CDP)

Survival (%)

8,341 men with previous myocardia...
Nicotinic Acid Evidence:
Secondary Prevention
HDL-Atherosclerosis Treatment Study (HATS)
160 men with CAD, low HDL-C, and ...
Nicotinic Acid Evidence:
Secondary Prevention
Atherothrombosis Intervention in Metabolic Syndrome with
Low HDL/High Trigly...
Nicotinic Acid Evidence:
Secondary Prevention
Heart Protection Study 2-Treatment of HDL to Reduce the
Incidence of Vascula...
Cholesterol Ester Transfer Protein
Evidence:
Mechanism of Action
LDL-R

Liver

F
C

SR-B1

CE
CETP

CE
Bile

Vessel
Wall

...
Cholesterol Ester Transfer Protein
Evidence:
Secondary Prevention Management to Understand its
Investigation of Lipid Leve...
Cholesterol Ester Transfer Protein
Evidence:
Secondary Prevention
Dal-OUTCOMES Trial
15,871 patients with a recent ACS ran...
CHD Risk According to Triglyceride
Levels
Meta-analysis of 29 prospective studies evaluating the risk of CHD relative
to t...
Fibrate:
Mechanism of Action
TG
VLDL

LPL

+

Fibrate

+

Intestine
IDL

LDL-R

Liver

CE
Mature HDL

FC
Nascent
HDL

FC

...
Fibrate Evidence:
Effect on Lipid Parameters
180 patients with type IIa or IIb hyperlipidemia randomized to fenofibrate
(1...
% CHD Death/Nonfatal MI

Fibrate Evidence:
Primary and Secondary Prevention
42%

Treatment arm

22%

22

Placebo

22***

9...
Fibrate Evidence:
Primary Prevention
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)
9,795 diabetic patien...
Fibrate Evidence:
Primary and Secondary Prevention
Action to Control Cardiovascular Risk in Diabetes (ACCORD)
Lipid Trial
...
Effect of Pharmacotherapy
on Lipid Parameters
TC

LDL-C

HDL-C

TG

Patient
tolerability

- 19-37%

- 25-50%

+ 4-12%

- 1...
Omega-3 Fatty Acids Evidence:
Effect on Lipid Parameters
27 patients with hypertriglyceridemia and low HDL-C treated with ...
Omega-3 Fatty Acids Evidence:
Primary and Secondary Prevention
Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS...
Omega-3 Fatty Acids Evidence:
Primary and Secondary Prevention
Outcome Reduction with Initial Glargine Intervention (ORIGI...
Omega-3 Fatty Acids
Evidence:
Secondary Prevention
Diet and Reinfarction Trial (DART)

All cause mortality (%)

2,033 men ...
Omega-3 Fatty Acids
Evidence:
Secondary Prevention della Sopravvivenza nell’Infarto
Gruppo Italiano per lo Studio
miocardi...
Omega-3 Fatty Acids
Evidence:
Secondary Prevention
OMEGA Trial

Rate of reinfarction,
stroke, or death* (%)

3,827 patient...
Risk Assessment for
LDL-C Lowering
A risk assessment tool* is needed for individuals with >2 RFs
10-year CHD Risk
0

10

2...
Risk Stratification:
Framingham Risk Score On Line
Calculator

Source: Expert Panel on Detection, Evaluation, and Treatmen...
Risk Stratification:
Framingham Risk Score for Men
Step 1: Age
Points
Years Points
20-34
35-39

-9
-4

40-44
45-49
50-54
5...
Risk Stratification:
Framingham Risk Score for Women
Step 1: Age
Points
Years Points
20-34
35-39

-7
-3

40-44
45-49
50-54...
Risk Stratification:
Reynolds Risk Score On Line Calculator

In addition to information collected as part of the Framingha...
ATP III LDL-C Goals and
Cut-points for Drug Therapy
Risk Category

Consider
Drug Therapy

LDL-C Goal

Initiate TLC

High r...
ATP III Classification of Other Lipoprotein
Levels Total Cholesterol
HDL-Cholesterol
Level (mg/dl)

Classification

Level ...
AHA Primary Prevention of CV Disease in DM
Cholesterol Recommendations
Primary Prevention
• In adult patients, lipid level...
AHA Primary Prevention of CV Disease in DM
Cholesterol Recommendations (Continued)
Primary Prevention
• In those >40 years...
AHA and ADA Primary Prevention of CV Disease
in DM Cholesterol Recommendations
Primary Prevention
• The ADA and AHA sugges...
ADA Cholesterol Recommendations for
Patients with Diabetes Mellitus
Primary Prevention
• In most adult patients, a fasting...
ADA Cholesterol Recommendations for
Patients with Diabetes Mellitus (Continued)
Primary and Secondary Prevention
• Statin ...
ADA Cholesterol Recommendations for
Patients with Diabetes Mellitus (Continued)
Primary and Secondary Prevention
• In indi...
ADA Cholesterol Recommendations for
Patients with Diabetes Mellitus (Continued)
Primary Prevention
• Triglyceride levels <...
Cholesterol Management
Recommendations (Continued)
Secondary Prevention
A lipid profile should be established in all patie...
Cholesterol Management
Recommendations (Continued)
Secondary Prevention
I IIa IIb III

I IIa IIb III

In addition to thera...
Cholesterol Management
Recommendations (Continued)
Secondary Prevention
I IIa IIb III

I IIa IIb III

I IIa IIb III

Patie...
Cholesterol Management
Recommendations (Continued)
I IIa IIb III

Secondary Prevention
It is reasonable to treat very high...
Cholesterol Management
Recommendations (Continued)
Secondary Prevention
I IIa IIb III

For patients who continue to have a...
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  • Classes of lipoproteins include LDL (low density lipoprotein), HDL (high density lipoprotein), VLDL (very low density lipoprotein), and chylomicrons.
  • 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.
  • 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.
  • In this study, Ford and colleagues calculated the prevalence of favorable total cholesterol status by assigning participants to low risk status (total cholesterol &lt; 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.
  • This graph demonstrates the relative risk for coronary heart disease relative to the LDL-C level.
  • There are many pharmacologic and dietary strategies to lower LDL-C levels.
  • Statins inhibit the HMG-CoA reductase enzyme, leading to reduced hepatic intracellular cholesterol production.
  • 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 &lt;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 0.50-0.83], 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.
  • Data from the main primary prevention trials (prior to publication of the MEGA and JUPITER trials) are displayed here.
  • 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.
  • 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 &lt;130 mg/dL that was screened to identify patients with a baseline hs-CRP level &gt;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.
  • 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, 0.57-0.95; 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 &gt;3x the upper limit of normal with atorvastatin as compared to placebo (2.5% vs 0.6%; P&lt;.001).
  • 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=0.005. This effect of intensive statin therapy set a new benchmark for aggressive early LDL-C lowering in acute coronary syndromes.
  • 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.
  • 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 5.5-8.0 mmol/L (212-309 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&lt;0.001).
  • 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 &lt;240 mg/dL and the LDL-C levels ranged between 115-174 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).
  • 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.
  • 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 &lt;100 mg/dL.
  • 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.
  • 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 &lt;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.
  • 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, 0.78-1.01, 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.
  • 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.
  • 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.
  • 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
  • The incidence of very high transaminases or myositis is relatively low with statin therapy.
  • Certain medications and medical conditions can raise the effective blood level of statins, thus potentiating their risk of myopathy.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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&lt;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 (0.0111 versus 0.0058 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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&lt;0.001).
  • 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.
  • 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.
  • 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.
  • 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 350-499 mg/dL and group B included 92 patients with triglyceride levels of 500-1500 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.
  • 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.
  • 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 0.75-1.05; 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.
  • 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.
  • 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.
  • Omega 3 fatty acids are another strategy available to lower triglyceride levels.
  • 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).
  • 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. 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).
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 4 acc prevention cholesterol

    1. 1. The Evidence for Current Cardiovascular Disease Prevention Guidelines: Cholesterol Management American College of Cardiology Evidence and Subcommittee Best Practice Quality Initiative Guidelines and Prevention Committee
    2. 2. Classification of Recommendations and Levels of Evidence *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Even though randomized trials are not available, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. †In 2003, the ACC/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines and will allow queries at the individual recommendation level.
    3. 3. Icons Representing the Classification and Evidence Levels for Recommendations I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III
    4. 4. Evidence for Current Cardiovascular Disease Prevention Guidelines Cholesterol, Cholesterol Therapies, and Cholesterol Guidelines
    5. 5. Lipoprotein Classes Chylomicrons, VLDL, and their catabolic remnants LDL HDL > 30 nm 20–22 nm 9–15 nm Potentially pro-inflammatory Potentially anti-inflammatory Sources: P. Barter. Role of Lipoproteins in Inflammation presentation, 2001. Available at http://www.lipidsonline.org/slides/slide01.cfm?&tk=18&dpg=3&x=293&43416. Doi H et al. Circulation 2000;102:670-676 Colome C et al. Atherosclerosis 2000;149:295-302 Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994
    6. 6. Role of Lipoproteins in Atherogenesis High plasma LDL HDL LDL infiltration into intima Adherence of platelets ( -) Endothelial injury LDL + VLDL Liver Cholesterol excreted LCAT APO-A1 Oxidative modification of LDL + Macrophages Foam cells Fatty streak Other growth factors Release of PDGF 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
    7. 7. Attributable Risk Factors for a First Myocardial Infarction INTERHEART Study 100 90 PAR (%) 80 60 40 50 36 20 0 33 14 Smoking 12 Fruits/ Exercise Veg 18 7 Alcohol Hypertension 20 10 Diabetes Abdominal Psychoobesity 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;364:937-952
    8. 8. Change in Total Cholesterol Levels in the United States Over Time National Health and Nutrition Examination Survey (NHANES) Total Cholesterol mg/dl (mmol/L) age-adjusted percentage 100% 90% 80% 70% 60% 50% 40% >240 mg/dL (>6.21 mmol/L) 200-240 mg/dL (5.17-6.21 mmol/L) 30% <200 mg/dL (<5.17 mmol/L) 20% 10% 0% Source: Ford ES et al. Circulation 2009;120:1181-1188
    9. 9. Coronary Heart Disease Risk According to LDL-C Level Relative Risk for Coronary Heart Disease (Log Scale) 3.7 2.9 2.2 1.7 1.3 1.0 40 70 100 130 160 190 LDL-Cholesterol (mg/dL) CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol Source: Grundy S et al. Circulation 2004;110:227-239
    10. 10. Therapies to Lower Levels of LDL-C Class 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMGCoA) reductase inhibitors [Statins] Bile acid sequestrants Cholesterol absorption inhibitor Nicotinic acid Dietary Adjuncts Drug(s) Atorvastatin (Lipitor) Fluvastatin (Lescol XL) Lovastatin (Mevacor) Pitavastatin (Livalo) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor) Cholestyramine (Questran) Colesevelam (Welchol) Colestipol (Colestid) Ezetimibe (Zetia) Niacin Soluble fiber Soy protein Stanol esters
    11. 11. HMG-CoA Reductase Inhibitor: Mechanism of Action Inhibition of the cholesterol biosynthetic pathway Squalene synthase HMG-CoA Reductase Acetyl CoA HMGCoA Mevalonate Farnesyl pyrophosphate Farnesyltransferase Dolichol Squalene Cholesterol E,E,E-Geranylgeranyl pyrophosphate Farnesylated proteins Geranylgeranylated proteins Ubiquinones
    12. 12. HMG-CoA Reductase Inhibitor: Mechanism of Action VLDL Cholesterol synthesis LDL receptor (B–E receptor) synthesis Intracellular Cholesterol VLDL RR VLDL Apo B Apo E LDL-R–mediated hepatic uptake of LDL and VLDL remnants Serum LDL-C LDL Apo B Serum VLDL remnants Serum IDL Hepatocyte Systemic Circulation The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which stimulates upregulation of the LDL receptor and increases uptake of non-HDL particles from the systemic circulation HDL=High density lipoprotein, LDL=Low density lipoprotein Source: McKenney JM. Selecting Successful Lipid-lowering Treatment presentation, 2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=4.
    13. 13. HMG-CoA Reductase Inhibitor: Dose-Dependent Effect The Rule of 6’s Lovastatin 20/80* 28 Pravastatin 20/40* 12 27 6 35 Simvastatin 20/80* Fluvastatin 20/80* 19 12 12 37 Atorvastatin 10/80* 18 46 Rosuvastatin 10/20† 6 32 Pitavastatin 1/4‡ 0 10 11 20 30 40 50 60 Each doubling of the statin dose produces an approximate 6% reduction in the LDL-C level Sources: *Illingworth DR. Med Clin North Am 2000;84-23-42 † Crestor Package Insert. http://www1.astrazeneca-us.com/pi/crestor.pdf ‡ Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf
    14. 14. HMG-CoA Reductase Inhibitor: Reduction in LDL-C A meta-analysis of 164 trials*†‡ Statin 10 mg/d 20 mg/d 40 mg/d 80 mg/d Atorvastatin 69 (37) 80 (43) 91 (49) 102 (55) Fluvastatin 29 (15) 39 (21) 50 (27) 61 (33) Lovastatin‡ 39 (21) 54 (29) 68 (37) 83 (45) Pravastatin 37 (20) 45 (24) 53 (29) 62 (33) Rosuvastatin§ 80 (43) 90 (48) 99 (53) 108 (58) Simvastatin 51 (27) 60 (32) 69 (37) 78 (42) *Standardized to LDL-C 186 mg/dL (mean concentration in trials) before Rx.† Independent of pre-Rx LDL-C ‡ Maximum dose of 80 mg/day administered as two 40-mg tablets § Not FDA approved at 80 mg/day #Data presented as absolute reductions in LDL-C* (mg/dL) and percent reductions in LDL-C (in parentheses) ‡ Although not included in this analysis, pitavastatin would be expected to achieve a 32%, 36%, and 43% mean reduction in LDL-C levels at the 1 mg, 2 mg, and 4 mg daily doses, respectively FDA=Food and Drug Administration, LDL-C=Low density lipoprotein cholesterol, Rx=Treatment Sources: Law MR et al. BMJ 2003;326:1423-1427 Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf
    15. 15. 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 2002 ALLHAT - LLA 1996 CARE 2002 ASCOT- LLA 1998 AFCAPS/TEXCAPS 2004 PROVE- IT 1998 LIPID 2004 A to Z 2001 MIRACL 2005 TNT 2002 HPS 2005 IDEAL 2008 JUPITER 2010 SEARCH
    16. 16. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention West of Scotland Coronary Prevention Study (WOSCOPS) 6,595 men with moderate hypercholesterolemia randomized to pravastatin (40 mg) or placebo for 5 years Rate of MI or CHD death (%) 31% RRR 9 7.5 6 5.3 3 0 P<0.001 Placebo Pravastatin A statin provides significant benefit in those with average cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Shepherd J et al. NEJM 1995;333:1301-1307
    17. 17. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention West of Scotland Coronary Prevention Study (WOSCOPS) Long-term follow-up at 5 and 10 years after conclusion of the study RRR=27%, p<0.001 RRR=18%, p<0.02 A statin provides long-term benefit in those with average cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Ford I et al. NEJM 2007;357:1477-1486
    18. 18. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS) 6,605 patients with average LDL-C levels randomized to lovastatin (2040 mg) or placebo for 5 years Rate of MI, unstable angina, or SCD (%) 37% RRR 6 5.5 4 3.5 2 0 P<0.001 Placebo Lovastatin A statin provides benefit in those with average LDL-C levels LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RRR=Relative risk reduction, SCD=Sudden cardiac death Source: Downs JR et al. JAMA 1998;279:1615–1622
    19. 19. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Arm (ALLHAT-LLA) Cumulative rate % 10,355 patients with HTN and >1 CHD risk factor randomized to pravastatin (40 mg) or usual care for 5 years 18 15 12 9 6 3 0 Pravastatin Usual care 32% cross-over among patients with CHD RR, 0.99; P=0.88 1 2 3 Years 4 5 6 The failure to demonstrate benefit with a statin may be the result of a high rate of cross over CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk Source: ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007
    20. 20. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA) Cumulative incidence of MI and fatal CHD (%) 10,305 patients with HTN randomized to atorvastatin (10 mg) or placebo for 5 years 4 3 Atorvastatin 90 mg/dl* Placebo 126 mg/dl* 36% RRR 2 1 0 0.0 P=0.0005 0.5 1.0 1.5 2.0 Follow-up (yr) 2.5 3.0 3.5 A statin provides significant benefit in moderate- to high-risk individuals by lowering LDL-C levels below current goals *Post-treatment LDL-C level CHD=Coronary heart disease, HTN=Hypertension, LDL-C=Low density lipoprotein cholesterol, RRR=Relative risk reduction Source: Sever PS et al. Lancet. 2003;361:1149-1158
    21. 21. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Relationship between LDL-C levels and event rates in select primary prevention statin trials CHD event rate (%) 10 Statin 8 Placebo WOSCOPS WOSCOPS 6 AFCAPS AFCAPS 4 ASCOT 2 ASCOT 0 –1 P=0.0019 55 75 95 115 135 155 175 195 LDL cholesterol (mg/dL) AFCAPS= Air Force/Texas Coronary Atherosclerosis Prevention Study, ASCOT= AngloScandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, LDL-C=Low density lipoprotein cholesterol, WOSCOPS= West of Scotland Coronary Prevention Study Source: O’Keefe JH Jr et al. JACC 2004;43:2142-2146
    22. 22. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial 7,832 men (age 40-70 years) and postmenopausal women (up to age 70 years) with total cholesterol levels of 220-270 mg/dL randomized to pravastatin (10-20 mg) or placebo for 5.3 years Number of adverse CV events* per 1000 person years 33% RRR 6 5.0 4 3.3 2 0 P=0.01 Placebo Pravastatin A statin provides benefit in those with high cholesterol levels *Composite of cardiac and sudden death, myocardial infarction, angina, and cardiac or vascular intervention CV=Cardiovascular Source: Nakamura H et al. Lancet 2006;368:1155-63
    23. 23. HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Cumulative incidence of CV death, MI, stroke, hospitalization for unstable angina, and arterial revascularization 0.00 0.04 0.08 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* Rosuvastatin Placebo 44% RRR P<0.00001, NNT=25 0 1 2 3 Follow-up (years) 4 A statin provides benefit in those with elevated hs-CRP levels *The study was stopped prematurely after 1.9 years CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction Ridker PM et al. NEJM 2008;359:2195-2207
    24. 24. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial event 3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo for 16 weeks Combined CV rate (%)* 15 15 17.4% 14.8% Placebo Atorvastatin 10 10 5 5 0 0 0 RR=0.84, P=0.048 4 8 Weeks 12 16 Acute intensive statin therapy provides significant CV benefit *Includes death, MI resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. ACS=Acute coronary syndrome, CV=Caradiovascular Source: Schwartz GG et al. JAMA 2001;285:1711-1718
    25. 25. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study Recurrent MI, cardiac death, UA, revascularization, or stroke 4,162 pts with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months 30 16% RRR Pravastatin 25 Atorvastatin 20 15 10 5 0 P=0.005 3 6 9 12 15 18 21 24 27 30 Follow-up (months) Acute intensive statin therapy provides significant CV benefit ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction, UA=Unstable angina Source: Cannon CP et al. NEJM 2004;350:1495-1504
    26. 26. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Aggrastat to Zocor (A to Z) Trial 4,162 patients with an ACS randomized to simvastatin (80 mg) or simvastatin (20 mg) for 24 months Cumulative event rate (%)* 20 Placebo/Simvastatin 20 mg/day 15 Simvastatin 40/80 mg/day 10 5 0 HR=0.89, P=0.14 0 4 8 12 16 Time from randomization (months) 20 24 Acute intensive statin therapy does not provide CV benefit *Includes CV death, MI, readmission for an ACS, and CVA ACS=Acute coronary syndrome, CV=Cardiovascular, CVA=Cerebrovascular accident, MI=Myocardial infarction Source: de Lemos JA et al. JAMA 2004;292:1307-1316
    27. 27. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Scandinavian Simvastatin Survival Study (4S) 4,444 patients with angina pectoris or previous MI randomized to simvastatin (20-40 mg) or placebo for 5.4 years 30% RRR Mortality (%) 12 11.5 8.2 8 4 0 P<0.001 Placebo Simvastatin A statin provides significant benefit in those with average LDL-C levels LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RRR=Relative risk reduction Source: 4S Group. Lancet 1994;344:1383–1389
    28. 28. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Cholesterol and Recurrent Events (CARE) Study 4,159 patients with a history of MI randomized to pravastatin (40 mg) or placebo for 5 years Rate of MI or CHD death (%) 24% RRR 15 13.2 10.2 10 5 0 P=0.003 Placebo Pravastatin A statin provides significant benefit in those with average cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Srouce: Sacks FM et al. NEJM 1996;335:1001–1009
    29. 29. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study 9,014 patients with a history of MI or hospitalization for unstable angina randomized to pravastatin (40 mg) or placebo for 6.1 years 24% RRR CHD Death (%) 9 8.3 6.4 6 3 0 P<0.001 Placebo Pravastatin A statin provides significant benefit across a broad range of cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: LIPID Study Group. NEJM 1998;339:1349–1357
    30. 30. 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) <100 282 (16.4%) 668 (18.9%) 871 (24.7%) ≥130 1083 (21.6%) 1356 (26.9%) All patients 2033 (19.8%) Statin Worse 358 (21.0%) 100–129 Statin Better Placebo (n = 10,267) 2585 (25.2%) 0.76 (0.72–0.81) P<0.0001 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
    31. 31. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) CHD death, non-fatal MI, stroke (%) 5,804 patients aged 70-82 years with a history of, or risk factors for, vascular disease randomized to pravastatin (40 mg) or placebo for 3.2 years 20 Placebo 10 Pravastatin 15% RRR, P=0.014 0 0 1 2 Years 3 4 A statin provides CV benefit in older men CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: Shepherd J et al. Lancet 2002;360:1623-1630
    32. 32. HMG-CoA Reductase Inhibitor Evidence: 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 Major CV Event* (%) 0.15 22% RRR Atorvastatin (10 mg) 0.10 Atorvastatin (80 mg) 0.05 P<0.001 0.00 0 1 2 3 Years 4 5 6 High-dose statin therapy provides benefit in chronic CHD *Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: LaRosa JC et al. NEJM 2005;352:1425-35
    33. 33. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial Cumulative Hazard (%) 8,888 patients with a history of acute MI randomized to atorvastatin (80 mg) or simvastatin (20 mg) for 5 years 12 Simvastatin (20 mg) 8 Atorvastatin (80 mg) 4 HR=0.89, P=0.07 0 1 2 3 4 5 Years Since Randomization High-dose statin therapy does not provide CV benefit after a MI *Includes coronary death, hospitalization for nonfatal acute MI, or cardiac arrest with resuscitation CV=Cardiovascular, HR=Hazard ratio, MI=Myocardial infarction Source: Pedersen TR et al. JAMA 2005;294:2437-2445
    34. 34. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Relationship between LDL-C levels and event rates in secondary prevention statin trials of patients with stable CHD 30 Statin Placebo Event (%) 25 4S 4S 20 LIPID CARE CARE HPS HPS TNT (atorvastatin 10 mg/d) TNT (atorvastatin 80 mg/d) LIPID 15 10 5 0 0 70 90 110 130 150 LDL-C (mg/dL) 170 190 210 CARE=Cholesterol and Recurrent Events Trial, CHD=Coronary heart disease, HPS=Heart Protection Study, LDL-C=Low density lipoprotein cholesterol, LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease, 4S=Simvastatin Survival Study, TNT=Treating to New Targets Source: LaRosa JC et al. NEJM 2005;352:1425-1435
    35. 35. HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) 12,064 patients with a history of MI randomized to simvastatin (80 mg) or simvastatin (20 mg) for a mean of 6.7 years * High-dose statin therapy does not provide CV benefit after a MI *Includes coronary death, myocardial infarction, stroke, or arterial revascularization CHD=Coronary heart disease, MI=Myocardial infarction Source: SEARCH Collaborative Group. Lancet 2010;376:1658-1669
    36. 36. HMG-CoA Reductase Inhibitor Evidence: Degree of Benefit in Prevention Types Meta-analysis of randomized controlled trials comparing risk reductions between primary and secondary prevention patients Relative Risk Reduction Absolute Risk Reduction Number Needed To Treat Primary Secondary Primary Secondary 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 NA 61 NA PCI or CABG 33.8 20.3 1.08 2.7 93 37 CABG=Coronary artery bypass graft surgery, CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, PCI=Percutaneous coronary intervention Source: Thavendiranathan P et al. Arch Intern Med 2006;166:2307-2313
    37. 37. HMG-CoA Reductase Inhibitor Evidence: Effect of Intensive Therapy Magnitude of event reduction among trials of intensive statin therapy Trial Population Duration (years) LDL-C Reduction (mg/dL) RR in Primary End Point (%) RR in MI or CHD Death (%) PROVE ITTIMI 22 ACS (N = 4162) 2 33 16 16 A to Z ACS (N = 4497) 2 14 11 15 TNT Stable CAD (N =10,001) 5 24 22 21 IDEAL Stable CAD (N = 8888) 5 23 11 11 Note: SI conversion factor: To convert LDL-C to mmol/L, multiply by 0.0259 ACS=Acute coronary syndrome, CAD=Coronary artery disease, CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RR=Relative reduction Source: Cannon CP et al. JAMA 2005;294:2492-2494
    38. 38. 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 21% relative risk reduction per mmol/L 15 Statin  16% relative risk reduction per 0.5 mmol/L 10 More statin 0 Five year risk of a major vascular event, % 20 Control 0 1 2 3 4 5 LDL cholesterol level (mmol/L) There is a proportionate reduction in CV events with greater cholesterol reduction LDL- CV=Cardiovascular, LDL=Low density lipoprotein Source: Cholesterol Treatment Trialists’ Collaboration. Lancet 2010;376:1670-1681
    39. 39. HMG-CoA Reductase Inhibitor: Adverse Effects 74,102 subjects in 35 randomized clinical trials with statins • 1.4% incidence of elevated hepatic transaminases (1.1% incidence in control arm) • Dose-dependent phenomenon that is usually reversible Hepatocyte • 15.4% incidence of myalgias* (18.7% incidence in control arm) • 0.9% incidence of myositis (0.4% incidence in control arm) • 0.2% incidence of rhabdomyolysis (0.1% incidence in control arm) Skeletal myocyte *The rate of myalgias leading to discontinuation of atorvastatin in the TNT trial was 4.8% and 4.7% in the 80 mg and 10 mg arms, respectively Source: Kashani A et al. Circulation 2006;114:2788-2797
    40. 40. HMG-CoA Reductase Inhibitor: Adverse Effects Risk factors for the development of myopathy* Concomitant Use of Meds Other Conditions Fibrate Advanced age (especially >80 years) Nicotinic acid (Rarely) Women > Men especially at older age Cyclosporine Small body frame, frailty Antifungal azoles** Multisystem disease‡ Macrolide antibiotics† Multiple medications HIV protease inhibitors Perioperative period Nefazadone Alcohol abuse Verapamil, Amiodarone Grapefruit juice (>1 quart/day) *General term to describe diseases of muscles **Itraconazole, Ketoconazole † Erythromycin, Clarithromycin ‡Chronic renal insufficiency, especially from diabetes mellitus Source: Pasternak RC et al. Circulation 2002;106:1024-1028
    41. 41. Bile Acid Sequestrant: Mechanism of Action Gall Bladder ↑ Cholesterol 7-α hydroxylase ↑ Conversion of cholesterol to BA ↑ BA Secretion Bile Acid Enterohepatic Circulation Terminal Ileum ↑ BA Excretion Reabsorption of bile acids Liver ↑ LDL Receptors ↑ VLDL and LDL removal ↓ LDL-C BA=Bile acid, LDL-C=Low density lipoprotein cholesterol, VLDL=Very low density lipoprotein
    42. 42. Bile Acid Sequestrant Evidence: Efficacy at Reducing LDL-C 15 LDL-C HDL-C TG 10 % Change from baseline at week 24 10 5 0 3 5 † 0 -1 -5 -10 -15 Placebo -15 * Colesevelam 3.8 grams/day -20 *P<0.001 vs placebo † P=0.04 vs placebo HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride Source: Insull W et al. Mayo Clin Proc 2001;76:971-982
    43. 43. Bile Acid Sequestrant Evidence: Primary Prevention Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) 3,806 men with primary hypercholesterolemia randomized to cholestyramine (24 grams) or placebo for 7.4 years Rate of MI or CHD death (%) 19% RRR 9 8.6 7.0 6 3 0 P<0.05 Placebo Cholestyramine A bile acid sequestrant provides benefit in those with high cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: The LRC-CPPT Investigators. JAMA 1984;251:351-364
    44. 44. Ezetimibe: Mechanism of Action Production in liver Absorption from intestine Bloodstream Dietary cholesterol LDL-C Cholesterol synthesis VLDL Biliary cholesterol Chylomicrons Fecal sterols and neutral sterols
    45. 45. 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 Mean % change from baseline to week 12 +5 0 +1.3 +0.4 –1.6 –5 –5.7 –10 Placebo –15 –16.9* Ezetimibe 10 mg –20 *p<0.01 compared to placebo HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Dujovne CA et al. Am J Cardiol 2002;90:1092-1097
    46. 46. 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% LDL-C=Low density lipoprotein cholesterol Sources: Kwiterovich Jr PO. Pediatrics 1995;96:1005-1009 Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214 Miettinen TA et al. Ann Med 2004;36:126-134
    47. 47. CHD Risk According to HDL-C Level Framingham Study CHD risk ratio 4.0 4.0 3.0 2.0 2.0 1.0 1.0 0 65 25 45 HDL-C (mg/dL) CHD=Coronary heart disease, HDLC=High-density lipoprotein cholesterol Source: Kannel WB. Am J Cardiol 1983;52:9B–12B
    48. 48. Nicotinic Acid: Mechanism of Action Mobilization of FFA Apo B VLDL TG synthesis Hepatocyte Apo B VLDL VLDL secretion Serum VLDL results in reduced lipolysis to LDL Serum LDL LDL HDL Systemic Circulation Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in reduced LDL cholesterol levels and increased HDL cholesterol levels FFA=Free fatty acid, HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride, VLDL=Very low density lipoprotein Source: McKenney JM. Selecting Successful Lipid-lowering Treatments presentation, 2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=14
    49. 49. Nicotinic Acid Evidence: Effect on Lipid Parameters 30% Mean change from Baseline 30 15% 20 10 22% 26% 30% HDL-C 10% 0 –9% -10 -20 –14% –5% –17% –11% -30 –21% LDL-C –28% -40 –35% -50 Dose (mg) –22% –39% 500 1000 1500 2000 2500 Triglyceride –44% 3000 HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride Source: Goldberg A et al. Am J Cardiol 2000;85:1100-1105
    50. 50. Nicotinic Acid Evidence: Secondary Prevention Coronary Drug Project (CDP) Survival (%) 8,341 men with previous myocardial infarction randomized to nicotinic acid (3 grams) or placebo for 15 years 100 90 80 70 60 5 0 40 Nicotinic Acid Nicotinic acid stopped Placebo P=0.0012 0 2 4 6 8 10 12 14 16 Years of follow-up Niacin provides long-term benefit following a MI MI=Myocardial infarction Source: Canner PL et al. JACC 1986;8:1245–1255
    51. 51. Nicotinic Acid Evidence: Secondary Prevention HDL-Atherosclerosis Treatment Study (HATS) 160 men with CAD, low HDL-C, and normal LDL-C randomized to simvastatin (1020 mg) + niacin (1000 mg bid), simvastatin (10-20 mg) + niacin (1000 mg bid) + antioxidants, antioxidants, or placebo for 3 years * ** Placebo (n=34) Niacin/Simvastatin (n=33) ** Placebo + Vitamins (n=39) Niacin/Simvastatin + Vitamins (n=40) A statin plus niacin provides benefit to men with CAD and low HDL-C levels *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;345:1583-1592
    52. 52. 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* 16.4% Primary outcome (%)** 20 Combination Therapy Monotherapy 16.2% 10 HR 1.02, p=0.79 0 0 1 2 3 4 Time (years) Niacin provides no benefit to those with CV disease and low HDL-C levels *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;365:2255-2267
    53. 53. Nicotinic Acid Evidence: Secondary Prevention Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial Major vascular events (%) 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* 15.0% 14.5% 15 Placebo Niacin/Laropiprant 10 5 HR 0.96, p=0.29 0 0 1 2 3 4 Years of follow-up Niacin provides no benefit to those with CV disease and low HDL-C levels *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, www.thrivestudy.org
    54. 54. Cholesterol Ester Transfer Protein Evidence: Mechanism of Action LDL-R Liver F C SR-B1 CE CETP CE Bile Vessel Wall LDL/VL DL LCAT FC HDL Free Cholesterol in Extrahepatic tissues 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
    55. 55. Cholesterol Ester Transfer Protein Evidence: Secondary Prevention Management to Understand its Investigation of Lipid Level Impact in Atherosclerotic Events (ILLUMINATE) Trial P=0.001 9 6 3 6.2 5.0 3 0 Atorvastatin Atorvastatin and Torcetrapib All-cause mortality (%) Primary end point** (%) 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* P=0.006 2 1.2 1 0 0.8 Atorvastatin Atorvastatin and Torcetrapib The CETP inhibitor, torcetrapib, is associated with increased CV risk *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;357:2109-2122
    56. 56. 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 Primary end point** (%) P=0.52 9 8.3 8.0 6 3 0 Placebo Dalcetrapib The CETP inhibitor, dalcetrapib, is associated with no CV benefit *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;357:2109-2122
    57. 57. 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 CHD=Coronary heart disease Source: Sarwar N et al. Circulation 2007;115:450-458
    58. 58. Fibrate: Mechanism of Action TG VLDL LPL + Fibrate + Intestine IDL LDL-R Liver CE Mature HDL FC Nascent HDL FC CE Macrophage 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
    59. 59. 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 50 Type IIa hyperlipidemia Type IIb hyperlipidemia Mean % change from baseline 40 30 20 10 0 LDL -30 -40 -50 TG HDL -10 -20 +15* +11* LDL -6* TG HDL -20* -38* -45* *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
    60. 60. % CHD Death/Nonfatal MI Fibrate Evidence: Primary and Secondary Prevention 42% Treatment arm 22% 22 Placebo 22*** 9% 17 66% 34% 2.7 4.1*** 13.6 15 13 8 2.7 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;317:1237-1245 Manninen V et al. Circulation 1992;85:37-45 BIP Study Group. Circulation 2000;102:21-27 Rubins HB et al. NEJM 1999;341:410-418
    61. 61. 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 11% RRR CHD Death or Nonfatal MI (%) 9 6 5.9 5.2 3 0 P=0.16 Placebo Fenofibrate A fibrate does not provide significant additional benefit* in diabetics *Unadjusted for concomitant statin use CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Keech A et al. Lancet 2005;366:1849-1861
    62. 62. 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 CV death, nonfatal stroke or nonfatal MI (%/year) 8% RRR 3 2.4 2.2 2 1 0 P=0.32 Placebo Fenofibrate On a background of statin therapy, a fibrate does not reduce CV events in diabetics CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: ACCORD study group. NEJM 2010;362:1563-1574
    63. 63. Effect of Pharmacotherapy on Lipid Parameters TC LDL-C HDL-C TG Patient tolerability - 19-37% - 25-50% + 4-12% - 14-29% Good - 13% - 18% + 1% - 9% Good Bile acid sequestrants - 7-10% - 10-18% + 3% Neutral or ­ Poor Nicotinic acid - 10-20% - 10-20% + 14-35% - 30-70% Reasonable to Poor - 19% - 4-21% + 11-13% - 30% Good Therapy Statins* Ezetimibe Fibrates *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
    64. 64. 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 Triglyceride 0 Total Cholesterol % Reduction -10 -20 -21* -30 -40 -50 -46* *P<0.05 HDL-C=High-density lipoprotein cholesterol Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731
    65. 65. 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 Years Omega-3 fatty acids provide CV benefit, particularly in secondary prevention *Composite of cardiac death, myocardial infarction, angina, PCI, or CABG CV=Cardiovascular, EPA=Eicosapentaenoic acid Source: Yokoyama M et al. Lancet 2007;369:1090-1098
    66. 66. 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 2% RRR CV death (%) 15 10 9.3 9.1 5 0 P=0.72 Placebo Omega 3 fatty acids Low dose omega-3 fatty acids do not provide CV benefit in at risk individuals CV=Cardiovascular, DM=Diabetes mellitus, IFG=Impaired fasting glucose, IGT=Impaired glucose tolerance Source: ORIGIN Trial Investigators. NEJM 2012;367:309-318
    67. 67. Omega-3 Fatty Acids Evidence: Secondary Prevention Diet and Reinfarction Trial (DART) All cause mortality (%) 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 8.0% 7.0% 6.0% 5.0% Omega-3 Fatty Acids 4.0% 3.0% Placebo 2.0% 1.0% 0.0% Omega-3 fatty acids reduce all cause mortality** in men after a MI *Corresponds to 2.5 grams of EPA (PUFA) **p<0.05 EPA=Eicosapentaenoic acid, MI=Myocardial infarction Source: Burr ML et al. Lancet 1989;2:757-761
    68. 68. Omega-3 Fatty Acids Evidence: Secondary Prevention della Sopravvivenza nell’Infarto Gruppo Italiano per lo Studio miocardico (GISSI-Prevenzione) Percent of patients 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 16 14 12 10 8 6 4 2 0 P=0.048 P=0.053 P=0.023 P=0.008 Omega-3 PUFA Placebo Death, NF MI, NF stroke (2 way) CV death, NF MI, and NF stroke Death, NF MI, NF stroke (4 way) CV death, NF MI, and NF stroke Omega-3 fatty acids provide significant CV benefit after a MI CV=Cardiovascular, MI=Myocardial infarction, NF=Non-fatal, PUFA=Polyunsaturated fatty acids Source: GISSI Investigators. Lancet 1999;354:447-455
    69. 69. Omega-3 Fatty Acids Evidence: Secondary Prevention OMEGA Trial Rate of reinfarction, stroke, or death* (%) 3,827 patients 3-14 days following a MI randomized to omega-3 fatty acids (460 mg EPA + 380 mg DHA) or placebo for 1 year 12 10.4 8.8 8 4 0 P=0.10 Placebo Fatty acids Omega-3 fatty acids provide no benefit following a MI in those with high utilization of risk reducing therapies *This is a secondary endpoint DHA=Docosahexaenoic acid, EPA=Eicosapentaenoic acid, MI=Myocardial infarction Source: Rauch B et al. Circulation 2010;122:2152-2159
    70. 70. Risk Assessment for LDL-C Lowering A risk assessment tool* is needed for individuals with >2 RFs 10-year CHD Risk 0 10 20 0-1 RFs ≥2 RFs CAD or Risk Equivalent** *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;285:2486-2497
    71. 71. 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. http://hp2010.nhlbihin.net/atpiii/calculator.asp
    72. 72. Risk Stratification: Framingham Risk Score for Men Step 1: Age Points Years Points 20-34 35-39 -9 -4 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 0 3 6 8 10 11 12 13 Step 3: HDL-C Points Points HDL-C (mg/dl) >60 -1 50-59 40-49 <40 0 1 2 Step 5: Smoking Status Points Age 20-39 Nonsmoker Smoker If untreated 0 0 1 1 2 0 1 2 2 3 Step 2: Total Cholesterol Points TC (mg/dl) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 <160 160-199 200-239 240-279 >280 0 4 7 9 11 0 3 5 6 8 0 2 3 4 5 0 1 1 2 3 0 0 0 1 1 Age 60-69 Age 70-79 0 8 0 5 0 3 0 1 0 1 Total Cholesterol HDL-C Systolic Blood Pressure Smoking Status If treated <120 120-129 130-139 140-159 >160 Age 50-59 Step 6: Sum of Age Points Step 4: SBP Points SBP (mm Hg) Age 40-49 Point Total Step 7: 10-year CHD Risk Point Total 10-year Risk Point Total 10-year Risk Point Total 10-year Risk <0 0 1 2 3 4 5 <1% 1% 1% 1% 1% 1% 2% 6 7 8 9 10 11 12 2% 3% 4% 5% 6% 8% 10% 13 14 15 16 >17 12% 16% 20% 25% >30% 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 http://www.framinghamheartstudy.org/risk/hrdcoronary.html.
    73. 73. Risk Stratification: Framingham Risk Score for Women Step 1: Age Points Years Points 20-34 35-39 -7 -3 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 0 3 6 8 10 12 14 16 Step 3: HDL-C Points Points HDL-C (mg/dl) >60 50-59 40-49 <40 -1 0 1 2 Step 5: Smoking Status Points Age 20-39 Nonsmoker Smoker Age 40-49 Age 50-59 Age 60-69 Age 70-79 0 9 0 7 0 4 0 2 0 1 Step 6: Sum of Points Age Total Cholesterol HDL-C Systolic Blood Pressure Smoking Status Step 4: SBP Points SBP (mmHg) If untreated If treated <120 120-129 130-139 140-159 >160 0 1 2 3 4 0 3 4 5 6 Step 2: Total Cholesterol Points TC (mg/dl) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 <160 160-199 200-239 240-279 >280 0 4 8 11 13 0 3 6 8 10 0 2 4 5 7 0 1 2 3 4 0 1 1 2 2 Point Total Step 7: 10-year CHD Risk Point Total 10-year Risk Point Total 10-year Risk Point Total 10-year Risk <9 9 10 11 12 13 14 <1% 1% 1% 1% 1% 2% 2% 15 16 17 18 19 20 21 3% 4% 5% 6% 8% 11% 14% 22 23 24 >25 17% 22% 27% >30% 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 http://www.framinghamheartstudy.org/risk/hrdcoronary.html.
    74. 74. 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. http://www.reynoldsriskscore.org/default.aspx
    75. 75. ATP III LDL-C Goals and Cut-points for Drug Therapy Risk Category Consider Drug Therapy LDL-C Goal Initiate TLC 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 (100-129 mg/dL: consider drug options) Moderate risk: 2+ risk factors* (10 year risk <10%) <130 mg/dL ≥130 mg/dL >160 mg/dL Lower risk: 0-1 risk factor* <160 mg/dL ≥160 mg/dL >190 mg/dL (160-189 mg/dL: LDL-C lowering drug optional) *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;110:227-239
    76. 76. ATP III Classification of Other Lipoprotein Levels Total Cholesterol HDL-Cholesterol Level (mg/dl) Classification Level (mg/dl) Classification <200 Desirable >40 Minimum goal* 200-239 Borderline High 40-50 Desired goal* >240 High >50 High Triglyceride Level (mg/dl) Classification <150 Normal 150-199 Borderline High 200-499 High >500 Very High *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;285:2486-2497
    77. 77. AHA Primary Prevention of CV Disease in DM Cholesterol Recommendations Primary Prevention • 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, HDLC=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Buse JB et al. Circulation 2007;115:114-126
    78. 78. 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;115:114-126
    79. 79. 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 200499 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, HDLC=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Sources: Buse JB et al. Circulation 2007;115:114-126 American Diabetes Association. Diabetes Care 2010;33:S11-61
    80. 80. 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
    81. 81. 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: o With overt CV disease o 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
    82. 82. 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
    83. 83. 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
    84. 84. 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 I IIa IIb III 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) Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
    85. 85. Cholesterol Management Recommendations (Continued) Secondary Prevention I IIa IIb III I IIa IIb III 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 I IIa IIb III Patients who have triglycerides >200 mg/dL should be treated with statins to lower non–HDL-C to <130 mg/dL Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
    86. 86. Cholesterol Management Recommendations (Continued) Secondary Prevention I IIa IIb III I IIa IIb III I IIa IIb III 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 Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
    87. 87. Cholesterol Management Recommendations (Continued) I IIa IIb III Secondary Prevention It is reasonable to treat very high-risk* patients with statin therapy to lower LDL-C to <70 mg/dL I IIa IIb III I IIa IIb III In patients who are at very high risk* and who have triglycerides >200 mg/dL, a non–HDL-C goal of <100 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 *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;58:2432-2446
    88. 88. Cholesterol Management Recommendations (Continued) Secondary Prevention I IIa IIb III 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 CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
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