New Concepts in the Evaluation and Treatment of Dyslipidemia

New Concepts in the Evaluation and Treatment of Dyslipidemia
Nathan D. Wong, PhD, FACC Professor and Director Heart Disease Prevention Program Division of Cardiology University of California, Irvine Past President, American Society for Preventive Cardiology

Lipoprotein Particles
VLDL Chylomicron 0.95 Only these lipoprotein particles found in plaque at biopsy. Chylomicron Remnants VLDL Remnants 1.006 IDL Density (g/ml) 1.019 LDL-R 1.050 By reporting single values for lipoprotein cholesterol levels, the traditional lipid panel implies that lipoproteins such as HDL, LDL,… are single entities. This slide illustrates that all lipid sub-fractions are present in a continuum of size and density, with an especially large gradient for the triglyceride-rich lipoproteins IDL, VLDL, and chylomicrons. Technologies that sort by particle size (NMR and GGE) cannot separate IDL and Lp(a) from LDL-R, as these particles have overlapping size. They do differ by density so ultracentrifugation is the best way to separate total LDL into its 3 components. Total LDL is made up of Lp(a), IDL and real LDL or R-LDL-R. We define R-LDL as total LDL-C minus Lp(a)-C minus IDL-C. Each requires different therapies, confers different risk and has different inheritance. Both Lp(a) and IDL are more atherogenic than LDL itself. They do not respond to statins and both are highly inherited and implicated in premature CAD. Lp(a), “the widowmaker” doubles risk but when another lipid risk factor, such as dense LDL, is also present the risk leaps to 25x. It may be useful to point out that Lp(a) cannot be accurately measured in most commercial laboratories because the immunoassay kits are sensitive to the size heterogeneity of the apoprotein(a) due to variation in the # of kringle repeats. Lp(a) rises in renal failure and is probably partly responsible for the terrible CAD in ESRD patients. High IDL requires combination therapy with a statin plus niacin. Density g/ml. Lp(a) and R-LDL are density range g/ml. Lp(a) and small/dense LDL overlap in the density range g/ml. Note that Lp(a) has overlaps with IDL and large R-LDL when GGE is used because of its different electrophoretic mobility – while the actual Lp(a) size is 21nm-25nm. Dense, small LDL is called Pattern B and increases risk 4x. Intermediately dense LDL is called Pattern A/B and doubles risk. HDL2 is the most protective HDL sub-fraction. HDL3 may be mildly protective to inert. You may have normal HDL but still have low HDL2 and not know it. Exercise and wine raise HDL2, as does niacin, fenofibrate and simvastatin. Atherogenic remnant lipoproteins include IDL and VLDL3 (small/dense). These are elevated in Metabolic Syndrome and NIDDM, and respond to low carbohydrate diets. If Lp(a), IDL or small/dense LDL pattern B are found, then first degree relatives should be tested. Note that large LDL may be confused with Lp(a) and IDL with size-based (vs. density based) separation methods as Lp(a) and IDL overlap with large R-LDL in size. 1.063 HDL2 Lp(a) 1.100 HDL3DL3 1.20 1000 5 10 20 40 60 80 Particle Size (nm)

The Apo B-containing (non-HDL) Lipoprotein Family: All Atherogenic
LDL Key Point: Apolipoprotein B (ApoB) and ApoAI are the major apolipoproteins of LDL and HDL, respectively.1 The Apo B-containing lipoproteins are present on several lipoproteins, as I mentioned before: LDL, VLDL, IDL, and lipoprotein(a). The cholesterol cargo in these Apo B lipoproteins can be calculated by the non-HDL cholesterol fraction, so non-HDL cholesterol is a surrogate for the Apo B-containing lipoproteins. In prospective population studies, Apolipoprotein B is a better predictor of cardiovascular risk than non-HDL cholesterol, but non-HDL cholesterol is a better predictor of cardiovascular risk than is LDL cholesterol. Additional Information: ApoB mediates the interaction between LDL and the arterial wall1 and is a component of all lipoprotein particles currently considered atherogenic.2 ApoB can be used to assess the number of LDL and very low-density (VLDL) particles present in plasma, as there is one molecule of ApoB on each particle. The amount of cholesterol on each particle is variable. Thus, ApoB is superior to LDL-C or non–HDL-C for estimating the plasma concentration of LDL and VLDL particles.1 ApoB-containing lipoproteins1 LDL—most common/most important IDL VLDL /VLDL remnants Chylomicron remnants Lp(a) *ApoB is a component of all lipoprotein particles currently considered atherogenic2 Apo = apolipoprotein; IDL = intermediate-density lipoprotein; VLDL = very low-density lipoprotein; Lp(a) = lipoprotein (a) 1. Olofsson SO et al. Vasc Health Risk Manag. 2007;3: 2. Grundy SM. Circulation. 2002;106: 3. Kunitake ST et al. J Lipid Res. 1992;33: Images available at: Accessed January Adapted with permission. 1. Olofsson SO et al. Vasc Health Risk Manag. 2007;3:491–502. 2. Grundy SM. Circulation. 2002;106:2526–2529. 3. Kunitake ST et al. J Lipid Res. 1992;33:1807–1816.

High Plasma Apo B Lipoprotein Levels Promote Atherogenesis
Rationale for therapeutic lowering of Apo B lipoproteins: decrease the probability of inflammatory response to retention Blood Apo B lipoprotein particles Modification Macrophage Monocytes bind to adhesion molecules Smooth muscle Foam cell Inflammatory response Key point: Lower levels of circulating Apo B lipoproteins lower probability of inflammatory response to retention. Background: Apo B lipoproteins are the mediators of the inflammatory process that lead to atherosclerosis. LDL, VLDL remnants, and chylomicron remnants (CM-r) in the circulation migrate through the arterial endothelium and into the intima of the arterial wall. LDL undergoes oxidative modification within the intima. Oxidized LDL promotes subsequent inflammatory inactivity in the intima by inducing endothelial cells to upregulate the vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Adhesion molecules promote the adherence of blood monocytes to endothelial cells and their migration into the subendothelial space. Monocytes differentiate into tissue macrophages and take up lipoprotein particles through scavenger receptors. Macrophages become lipid-laden foam cells, triggering the maladaptive inflammatory response. We know that high-plasma Apolipoprotein B levels are associated with increased risk of cardiovascular events. Apolipoprotein B is found on several atherogenic lipoproteins – LDL, VLDL, IDL, and lipoprotein(a). When these particles are elevated in the circulation, they may not be cleared by the LDL receptor. These particles, therefore, may transit through the endothelium. In the endothelium, these Apo B-containing lipoproteins may undergo chemical modification. Chemical modification includes: oxidation, glycation, and phospholipid modification by secretory PLA2 or phospholipase A2 and lipoprotein-associated phospholipase A2. These modified LDL particles can be taken up by the macrophage via several different receptors – oxidized LDL is incorporated by the scavenger receptor; the phospholipase A2-modified LDL particles are taken up by the putative M-type receptor; and the glycated particles could be oxidized, and they can also be taken up by the scavenger receptor. The loading of cholesterol into the macrophage can convert that macrophage into a pro-inflammatory type of macrophage that secretes inflammatory cytokines that can be released into the circulation, and generate a systemic inflammatory response that does identify individuals at increased risk for a cardiovascular event. Tabas I et al. Circulation. 2007;116: Merrilees MJ et al. J Vasc Res. 1993;30: Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15: Nakata A et al. Circulation.1996;94: Hoshiga M et al. Circ Res. 1995;77: Steinberg D et al. N Engl J Med. 1989;320: Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25: References: 1. Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116(16):1832–1844. 2. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340(2):115–126.

Lipid Atherogenesis Endothelial injury High plasma LDL HDL LDL + VLDL
Adherence of platelets LDL infiltration into intima LCAT APO-A1 Release of PDGF Oxidative modification of LDL Liver Other growth factors + Macrophages Foam cells Fatty streak Cholesterol excreted Advanced fibrocalcific lesion

Anti-atherosclerotic therapy
Unstable lesion lipid core adventitia Anti-atherosclerotic therapy Stable lesion lipid core adventitia From Davies et al (1998)

Proportion of U.S. Adults at Recommended Lipid Levels in NHANES 2003-2004
Ghandehari and Wong et al, Am Heart J 2008

Genetic Causes of Dyslipidemia
Type I – Familial Hyperchylomicronemia Fasting triglycerides > 1000 mg/dl Defect in lipoprotein lipase or apo CII Not necessarily at increased risk of CAD Type II - Familial Hypercholesterolemia (type II) LDL-C > 95th percentile for age and gender CAD in men by 3rd or 4th decade Defect in LDL receptor Autosomal dominant inheritance Prevalence 1:500 Familial Defective apo B 100 Defective apo B alters LDLr handling Previously undetecable from FH

Type III – Hyperlipoproteinemia Increased TC, VLDL, decreased HDL; Increased VLDL:TG Defect in apo E results in increased concentration of remnant particles Rare Type IV – Familial Hypertriglyceridemia Increased TC (due to VLDL), TG, decreased LDL, HDL Results from hepatic overproduction of VLDL Prevalence 1:100 – 1:50; Association with CAD not as strong as FH Heterogeneous inheritance Very sensitive to diet and EtOH Type V Increase in chylomicrons and VLDL

Familial Combined Hyperlipidemia Increased TC, LDL and/or triglycerides; decreased HDL Most common genetic dyslipidemia: prevalence 1:50 Heterogenous inheritance Accounts for 10-20% of patients with premature CAD Defects in HDL Metabolism Most often low HDL is secondary to other dyslipidemia Not all associated with increased CAD risk (e.g. apo AIMilano) Tangier’s Disease CETP defects result in increased HDL

Data from the Framingham Heart Study show the continuous relationship between risk of developing CVD over 8 years and levels of cholesterol.9 Other assumptions for this model are that the patient was a 40-year-old man, who was ECG left ventricular hypertrophy (LVH) negative, and with no glucose intolerance, and who was not a current smoker. As illustrated on this slide, the relationship between level of total cholesterol (TC) and CVD risk is graded and continuous. Risk is not confined to the upper centiles.9 9. Kannel WB. Importance of hypertension as a major risk factor in cardiovascular disease. In: Genest J, Koiw E, Kuchel O, eds. Hypertension. Physiopathology and Treatment. New York, NY: McGraw-Hill; 1977:

Total Cholesterol Distribution: CHD vs Non-CHD Population
Framingham Heart Study—26-Year Follow-up No CHD 35% of CHD Occurs in People with TC<200 mg/dL CHD Slide 3. Total cholesterol distribution: CHD vs non-CHD population In the Framingham Heart Study, as many as one third of all coronary heart disease (CHD) events occurred in individuals with total cholesterol <200 mg/dL. Considering that the average U.S. cholesterol level is approximately 210 to 220 mg/dL, almost half of all heart attack events and all stroke events that will occur in the United States next year will in fact occur among individuals with below-average lipid levels. For this reason, our research group has sought in our large-scale prospective epidemiologic studies to understand better other markers associated with cardiovascular risk. Reference: Castelli WP. Lipids, risk factors and ischaemic heart disease. Atherosclerosis 1996;124(Suppl):S1-9. Keywords: cholesterol distribution, Framingham Heart Study Slide type: graph 150 200 250 300 Total Cholesterol (mg/dL) Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 1996 Reprinted with permission from Elsevier Science.

Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal
12.50 11.91 11.91 14 9.05 10.7 12 11.24 10 6.6 5.53 14-y incidence rates (%) for CHD 8 6.56 3.83 4.85 6 4.67 2.06  260 4.15 4 3.77 2.78 230–259 2 200–229 Speaker’s Notes/Talking Points: Low high-density lipoprotein cholesterol (HDL-C) levels (< 40 mg/dL) are associated with an increased risk of coronary heart disease (CHD) even if the total cholesterol (Total-C) level is < 200 mg/dL. This slide shows the CHD incidence over 14 years among Framingham Study subjects who were aged 48–83 years at baseline.1 Among those with HDL-C levels < 40 mg/dL and Total-C < 200 mg/dL, 11.24% experienced a CHD event. This incidence was virtually the same as that (11.91%) for subjects with HDL-C levels between 40–49 mg/dL and Total-C  260 mg/dL. References 1. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA. 1986;256:2835–2838. Total-C (mg/dL) < 200 < 40 40–49 50–59  60 HDL-C (mg/dL) Risk of CHD by HDL-C and Total-C levels; aged 48–83 y Castelli WP et al. JAMA 1986;256:2835–2838

Triglyceride Level Is Significant CHD Risk Factor: Recent Meta-Analysis of 29 Studies (n=262,525) (Sarwar et al., Circulation 2007) Groups CHD Cases CHD Risk Ratio* (95% CI) Duration of follow-up ≥10 years <10 years Sex N=262,525 Male Female Fasting status Fasting Nonfasting Adjusted for HDL Yes Triglyceride Level Is Significant CVD Risk Factor: Recent Meta-Analysis of 29 Studies A recent meta-analysis by Sarwar and colleagues included 29 prospective studies, and was the largest and most comprehensive epidemiological assessment of the association between triglyceride values and coronary heart disease (CHD) risk in Western populations (262,525 participants; 10,158 CHD cases). A combined analysis of the 29 studies yielded an adjusted odds ratio of 1.72 (95% CI, 1.56–1.90) in a comparison of extreme thirds of usual triglyceride values (ie, individuals with usual log-triglyceride values in the top third of the population compared with those in the bottom third). This odds ratio was adjusted in all but one study for at least age, sex, smoking status, lipid concentrations, and most studies also adjusted for blood pressure. The above figure shows the CHD risk-ratio adjusted for several established risk-factors and grouped according to several study characteristics (ie, duration of follow-up, sex, fasting status, and adjusted for high-density lipoprotein [HDL]-cholesterol). The data indicate that the impact of triglycerides on CHD risk is similar in women and men regardless of duration of follow-up. The data suggest no important differences in the strength of associations between triglycerides and CHD in studies of fasting participants compared with studies of nonfasting participants. Finally, adjustment for HDL-cholesterol attenuated the magnitude of the association between triglyceride level and CHD risk. The conclusion of the study is that there is a strong and highly significant association between triglyceride value and CHD risk. Reference Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115: No Overall CHD Risk Ratioa 1.72 (1.56–1.90) 1 2 Decreased Risk Increased Risk aIndividuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most) CHD=coronary heart disease HDL=high-density lipoprotein Sarwar N, et al. Circulation. 2007;115: 14

How Can Hypertriglyceridemia be Atherogenic?
Triglyceride-rich lipoproteins carry cholesterol and promote atherosclerosis* Very–low-density lipoprotein (VLDL) is precursor to low-density lipoprotein (LDL) Hypertriglyceridemia (HTG) drives Cholesterol esters enrichment of VLDL (more atherogenic) ↓ LDL size (small, dense LDL are more atherogenic)* ↓ LDL-C (small, dense LDL carry less cholesterol)* ↓ High-density lipoprotein (HDL) size (small, dense HDL are unstable) HTG is linked to other proatherogenic states* Insulin resistance Proinflammatory state Prothrombotic state Prooxidative state Endothelial dysfunction How Can Hypertriglyceridemia be Atherogenic? One question sometimes posed by physicians is “Since it’s cholesterol (not triglycerides) that is deposited in the artery wall, why is hypertriglyceridemia atherogenic?” We can remind physicians that triglycerides are carried in atherogenic particles; the triglyceride-rich lipoproteins are VLDL, VLDL remnants, and IDL, which can be atherogenic. In addition, VLDL is a precursor of LDL (via intravascular remodeling) and in the presence of high triglyceride levels a smaller, denser LDL is produced; this is probably why non-HDL cholesterol is a stronger predictor of cardiovascular disease (especially when triglycerides levels are high) than is LDL cholesterol. Hypertriglyceridemia also tends to remodel HDL, resulting in a smaller HDL particle that tends to have a higher rate of apo A1 dissociation. High triglycerides are also linked to other pro-atherogenic states, such as insulin resistance. Triglyceride rich lipoproteins have also been shown to be proinflammatory, to increase reactive oxygen species, and to promote endothelial dysfunction. The take home concept is that hypertriglyceridemia predicts the presence of triglyceride-rich atherogenic particles that are important to the atherosclerotic process, and that hypertriglyceridemia alters the intravascular processing of LDL and HDL to smaller, denser particles. *Reasons why non–HDL-C is stronger than LDL-C as predictor of cardiovascular disease 15

Elevated Triglycerides Are Associated With Increased Small, Dense LDL Particles
Fewer Particles More Particles LDL= 130 mg/dL Apolipoprotein B More apolipoprotein B Cholesterol ester Elevated Triglycerides Are Associated With Increased Small, Dense LDL Particles Cholesterol is packaged into lipoproteins primarily in the form of cholesterol esters. Lipoproteins differ in size and cholesterol ester content. Small, dense low-density lipoprotein (LDL) particles are relatively poor in cholesterol esters, but there are more small LDL particles required to give any specific value for the total cholesterol in the LDL fraction. The number of particles is a predictor of risk and therefore the LDL-C measure can be misleading with regard to the risk contributed by these lipoproteins when small LDL are present. The LDL-C value measured in a standard lipid profile does not provide information about the size and atherogenicity of the LDL particle population. For example, a patient may have a normal LDL-C value, but the majority of cholesterol may be contained in small, dense LDL particles, thus placing this patient at higher risk for coronary heart disease. Triglyceride concentrations over 200 mg/dL almost always predict the presence of small, dense LDL particles. Reference Otvos JD, Jeyarajah ED, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol. 2002;90:22i-29i. Correlates with: TC 198 mg/dL LDL-C 130 mg/dL TG 90 mg/dL HDL-C 50 mg/dL Non–HDL-C 148 mg/dL Correlates with: TC mg/dL LDL-C mg/dL TG mg/dL HDL-C mg/dL Non–HDL-C 180 mg/dL Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i. TC=total cholesterol, LDL-C=low-density lipoprotein cholesterol, TG=triglycerides, HDL-C=high-density lipoprotein cholesterol 16

Why Is Small, Dense LDL More Atherogenic?
 Cholesterol per particle, BUT  Subendothelial penetration  Subendothelial binding  Oxidized/modified  LDL-receptor clearance Why Is Small, Dense LDL More Atherogenic? Small dense LDL particles don’t necessarily carry a lot of cholesterol, but because of their smaller size, they may have greater subendothelial penetration and probably bind to the matrix and arterial wall better. In addition, they may be modified and oxidized to a greater degree, which increases their uptake through non-traditional LDL receptor mechanisms, and they may actually have a decreased LDL receptor clearance rate compared to normal-sized LDL particles. In addition to the increased particle number seen with small, dense LDL, these characteristics combine to make this lipoprotein species more atherogenic. LDL=low-density lipoprotein 17

Non-HDL-Cholesterol and CVD Risk
Significance of Non-HDL-C LDL-C levels incompletely measure the total atherogenic burden When serum TG are >200 mg/dL, increased remnant atherogenic lipoproteins heighten risk beyond predicted by LDL-C Associated with substantially elevated VLDL-C VLDL-C and IDL-C are not accounted for by the calculation of LDL-C Non-HDL-C = cholesterol concentration of all atherogenic lipoproteins Miller M, et al. Am J Cardiol 2009;101:

Non-HDL Includes All Atherogenic Lipoprotein Classes
Non-HDL; Apo B-100—containing Atherogenic Lipoproteins Very–low-density lipoprotein (VLDL) Made in the liver Triglycerides (TG) >> cholesterol esters (CE) Carries lipids from the liver to peripheral tissues VLDL Intermediate-density lipoprotein (IDL) Formed from VLDL due to lipase removal of TG Also known as a VLDL remnant IDL Low-density lipoprotein (LDL) Formed from IDL due to lipase removal of TG CE >> TG Non-HDL Includes All Atherogenic Lipoprotein Classes There are 4 major classifications of lipoproteins present in plasma, shown here in order of their size. Very–low-density lipoprotein (VLDL) is released from the liver into the plasma Intermediate-density lipoprotein (IDL) and low-density lipoproteins (LDL) are products of lipolysis (removal of trigycerides [TG]) of VLDL. That is, as VLDL moves through the bloodstream, tissues selectively pull off the TGs (because fatty acids are energy and tissues need them). As TGs are pulled off, the VLDL particle shrinks, becoming IDL, and then TG removal from IDL converts it into LDL High-density lipoprotein (HDL) is the smallest lipoprotein. Instead of taking cholesterol from the liver to other tissues, it picks up cholesterol from these tissues and brings it to steriodogenic tissues, the liver, or the kidneys. That is why it is considered the “good” cholesterol VLDL, IDL, and LDL all contain apolipoprotein B, and together are considered non-HDL cholesterol LDL Lipoprotein (a) Formed from LDL w/addition of apolipoprotein A Atherogenic and prothrombotic Lp(a) High-density lipoprotein (HDL) Removes cholesterol from peripheral tissues HDL 19

Lp(a) in Atherogenesis: Another Culprit?
Identical to LDL particle except for addition of apo(a) Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although not all Accumulates in atherosclerotic plaque Binds apo B-containing lipoproteins and proteoglycans Taken up by foam cell precursors May interfere with thrombolysis Maher VMG et al. JAMA. 1995;274: Stein JH, Rosenson RS. Arch Intern Med. 1997;157:

Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort
10 5 3.6 2.7 2 1.9 1.8 1.8 1.2 1 RR 0.5 Lp(a) TC HDL-C HT GI Smoking 0.2 0.1 RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA. 1996;276:

Placebo - Statin outcome trials
Continuum of risk CORONA GISSI-HF (rosuvastatin) Heart failure 53.7 End stage High-risk CHD patients (high cholesterol) 4S (simvastatin) HPS Secondary prevention 22.6 Majority of CHD patients (broad range of cholesterol levels) 12.9 CARE (pravastatin) LIPID (pravastatin) Placebo MI rate per 100 subjects per 5 years 8.44 Relevance to Clinical Practice To date, we have accumulated data on the effectiveness of statin therapy on many patient populations. Future research will begin to focus on specific unanswered questions and effectiveness of individual statins in comparison to each other. PROSPER (pravastatin) Patients at high risk of CHD (high cholesterol) 7.9 Primary prevention WOSCOPS (pravastatin) 2.8 AFCAPS/TexCAPS (lovastatin) Patients at low risk of CHD (low HDL-C) JUPITER (rosuvastatin) 22

LDL cholesterol and benefit in clinical trials Is lower better ?
LDL-C achieved mg/dL (mmol/L) WOSCOPS – Placebo AFCAPS - Placebo ASCOT - Placebo AFCAPS - Rx WOSCOPS - Rx ASCOT - Rx 4S - Rx HPS - Placebo LIPID - Rx 4S - Placebo CARE - Rx LIPID - Placebo CARE - Placebo HPS - Rx 5 10 15 20 25 30 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) Event rate (%) 6 Secondary Prevention Primary Prevention Rx - Statin therapy PRA – pravastatin ATV - atorvastatin 200 (5.2) PROVE-IT - PRA PROVE-IT – ATV Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2): LaRosa JC et al. N Engl J Med 2005;352:e-version TNT – ATV10 TNT – ATV80 TNT A number of landmark studies have shown that the reduction of LDL-C with statin therapy improves cardiovascular morbidity and mortality in patients with and without established cardiovascular disease. In both primary and secondary prevention studies a greater reduction in LDL-C resulted in greater reductions in cardiovascular (CV) events. Achieving lower LDL-C levels is now increasingly accepted. The data clearly show that whether you have CV or not and whatever your baseline LDL-C is, however much you lower LDL-C you reduce CV risk and the lower you can get your LDL-C the better. The international guidelines for screening and intervention are based on evidence such as that presented together with epidemiological data. It is therefore reasonable that the achievement of evidence-based treatment guideline goals can be used as a good surrogate for outcomes data until that becomes available. References Ballantyne C. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. Sever, PS et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet 2003;361: Rosensen RS. Exp Opin Emerg Drugs 2004;9(2): LaRosa JC, Grundy SM, Waters DD et al. N Engl J Med 2005;352:e-version. Adapted from Am J Cardiol 1998;82:3Q-12Q with permission from Excerpta Medica Inc. JUPITER 23

Cholesterol Treatment Trialists’ (CCT) Collaboration: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis fo data from 90,056 participants in 14 randomized trials of statins (The Lancet 9/27/05) Over average 5 year treatment period (per mmol/L reduction—approx 40 mg/dl in LDL-C): 12% reduction in all-cause mortality 19% reduction in coronary mortality 23% reduction in MI or CHD death 17% reduction in stroke 21% reduction in major vascular events No difference in cancer incidence (RR=1.00). Statin therapy can safely reduce 5-year incidence of major coronary events, revascularization, and stroke by about 20% per mmol/L (about 38 mg/dl) reduction in LDL-C

HPS: First Major Coronary Event
Statin- Allocated (n = 10269) Placebo- Allocated (n = 10267) Type of Major Vascular Event Statin Better Placebo Better Coronary events Nonfatal MI 357 (3.5%) 574 (5.6%) Coronary death 587 (5.7%) 707 (6.9%) Subtotal: MCE 898 (8.7%) 1212 (11.8%) 0.73 (0.670.79) P < Revascularizations Coronary 513 (5.0%) 725 (7.1%) Noncoronary 450 (4.4%) 532 (5.2%) 0.76 (0.700.83) P < Subtotal: any RV 939 (9.1%) 1205 (11.7%) Allocation to simvastatin also produced an extreme 38% proportional reduction in incidence of first nonfatal myocardial infarction following randomization (357 [3.5%] simvastatin vs 574 [5.6%] placebo; p<0.0001). Combining this with the effect on coronary death rate, there was a 27% proportional reduction in the incidence rate of ‘major coronary events’ (MCE): (898 [8.7%] vs 1212 [11.8%]; p<0.0001). Simvastatin treatment also resulted in a highly significant 24% proportional reduction in the incidence rate of first revascularization procedure following randomization (939 [9.1%] simvastatin vs 1205 [11.7%] placebo; p<0.0001). A 30% proportional reduction in the incidence rate of coronary revascularization occurred (513 [5.0%] vs 725 [7.1%]; p<0.0001), and there was also a significant 16% proportional reduction in the incidence rate of noncoronary revascularization (450 [4.4%] vs 532 [5.2%]; p=0.006). Major vascular events of any kind were reported in significantly fewer patients allocated to simvastatin compared to placebo (2033 [19.8%] vs 2585 [25.2%]; p<0.0001). Any MVE 2033 (19.8%) 2585 (25.2%) 0.76 (0.720.81) P < 0.4 0.6 0.8 1.0 1.2 1.4 Heart Protection Study Collaborative Group. Lancet. 2002;360:722.

HPS—Simvastatin: Vascular Events by Baseline LDL-C
LDL-C (mg/dL) Statin (n = 10,269) Placebo (n = 10,267) <100 282 (16.4%) 358 (21.0%) 100–129 668 (18.9%) 871 (24.7%) 130 1083 (21.6%) 1356 (26.9%) All patients 2033 (19.8%) 2585 (25.2%) Event Rate Ratio (95% CI) Statin Better Statin Worse 0.76 (0.72–0.81) P < 0.4 0.6 0.8 1.0 1.2 1.4

Recurrent MI or Cardiac Death
HMG-CoA Reductase Inhibitor: Secondary Prevention Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study 4,162 patients with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months Follow-up (months) 30 25 20 15 10 5 P =0.005 Recurrent MI or Cardiac Death 16% RRR Atorvastatin Pravastatin ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Cannon CP et al. NEJM 2004;350:

Patients With CHD Events (%)
TNT: Rationale TNT Screening Patients With CHD Events (%) ? Atorvastatin 10 mg The primary hypothesis of the TNT study was that incremental reduction in cardiovascular risk can be achieved by lowering LDL-C levels beyond currently recommended minimum targets.1 Atorvastatin 80 mg (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2) LDL-C, mg/dL (mmol/L) Adapted from LaRosa et al. N Engl J Med. 2005:352: Reference 1. Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C, for the TNT Steering Committee Members and Investigators. Treating to New Targets (TNT) study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol. 2004;93:

TNT: Changes in LDL-C by Treatment Group
Baseline 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Mean LDL-C level = 101 mg/dL (2.6 mmol/L) Mean LDL-C (mg/dL) Mean LDL-C (mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L) During the open-label period, LDL-C was reduced by 35% in the overall patient population, from 152 mg/dL (3.9 mmol/L) to 98 mg/dL (2.6 mmol/L).1 Following randomization, mean LDL-C in the atorvastatin 10-mg group was maintained at approximately baseline level for the duration of the treatment period, with an average of 101 mg/dL (2.6 mmol/L) across the 5 years of follow-up.1 After 12 weeks of treatment, LDL-C was further reduced to a mean level of 77 mg/dL (2.0 mmol/L; P<.001) among patients receiving atorvastatin 80 mg.1 The LDL-C level in the 80-mg group remained relatively stable over the course of the study.1 P<.001 Screen 3 12 24 36 48 60 Final Study Visit (Months) LaRosa et al. N Engl J Med. 2005;352: Reference 1. LaRosa JC, Grundy SM, Waters DD, et al, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:

TNT: Primary Efficacy Outcome Measure: Major Cardiovascular Events*
0.15 Atorvastatin 10 mg Atorvastatin 80 mg Relative risk reduction 22% 0.10 Mean LDL-C level = 101 mg/dL Proportion of Patients Experiencing Major Cardiovascular Event 0.05 Mean LDL-C level = 77 mg/dL Over the course of the study, there was a highly significant reduction in the composite efficacy outcome of major cardiovascular events in the atorvastatin 80-mg group compared with the atorvastatin 10-mg group.1 The Kaplan-Meier analysis showed a hazard ratio of 0.78 (95% CI 0.69, 0.89; P<.001).1 This represented a 22% reduction in relative risk in the atorvastatin 80-mg group relative to the atorvastatin 10-mg group, over and above the low absolute event rate of 10.9% recorded in the atorvastatin 10-mg group.1 There was no statistical interaction for age or sex in the primary outcome measure.1 HR=0.78 (95% CI 0.69, 0.89); P<.001 1 2 3 4 5 6 Time (Years) * CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. LaRosa et al. N Engl J Med. 2005;352: Reference 1. LaRosa JC, Grundy SM, Waters DD, et al, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:

Meta analysis of moderate vs aggressive statin therapy
Coronary death or MI ACS Stable CHD Cannon et al (2006) JACC 48:438 31

Recent Coronary IVUS Progression Trials
Relationship between LDL-C and Progression Rate 1.8 CAMELOT placebo REVERSAL pravastatin 1.2 ACTIVATE placebo 0.6 REVERSAL atorvastatin Median change in percent atheroma volume (%) A-Plus placebo -0.6 ASTEROID rosuvastatin -1.2 50 60 70 80 90 100 110 120 Mean LDL-C (mg/dL) Nissen SE, Nicholls S et al. JAMA 2006;295:1555–1565 32

ASTEROID: Study Design
Patients (≥18 years) CAD, undergoing coronary angiography Target coronary artery: ≤50% reduction in lumen diameter of ≥40 mm segment Target segment for QCA: all segments >25% at baseline No cholesterol entry criteria Rosuvastatin 40 mg (n=349 for IVUS analysis; n=292 for QCA analysis) Visit: Week: 1 –6 2 3 13 4 26 5 39 6 52 7 65 8 78 9 91 10 104 IVUS QCA Lipids Eligibility assessment Lipids Lipids Tolerability Tolerability Lipids Tolerability Tolerability Tolerability IVUS QCA Lipids Tolerability 33

Change in Key IVUS Parameters
End Point Analysis: Change in Key IVUS Parameters Median atheroma volume in the most diseased 10-mm Median normalized TAV subsegment n=319 n=346 -1 -2 -3 -4 Change from baseline (%) -5 -6 -7 - 6.8% -8 * -9 - 9.1% -10 * *P<0.001 for difference from baseline. Wilcoxon signed rank test Adapted from Nissen et al. JAMA 2006;295(13): 34

Example of Regression of Atherosclerosis with Rosuvastatin in ASTEROID (measured by IVUS)
Sipahi I, Nicholls S, Tuzcu E, Nissen S. Interpreting the ASTEROID trial: Coronary atherosclerosis can regress with very intensive statin therapy. Cleve Clin J Med, 2006; 73: Reprinted with permission. Copyright 2006. Cleveland Clinic Foundation. All rights reserved. 35

A statin reduces adverse CV events in diabetics
Diabetes Mellitus: Effect of an HMG-CoA Reductase Inhibitor Meta-analysis of 18,686 patients with DM randomized to treatment with a HMG-CoA Reductase Inhibitor A statin reduces adverse CV events in diabetics Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2008;37:117-25

Residual CVD Risk in Statin vs Placebo Trials
Many CHD Events Still Occur in Statin-Treated Patients 25-40% CVD Reduction Leaves High Residual Risk 28.0 Placebo Statin Patients Experiencing Major CHD Events, % 19.4 12.3 10.2 8.7 5.5 6.8 15.9 13.2 11.8 10.9 7.9 Residual Cardiovascular Risk in Major Statin Trials. In all of these major statin trials,1-6 significant residual cardiovascular risk remains even after reducing LDL-C. According to Libby, in the best of circumstances, the decrease in cardiovascular events due to statin treatment still allows two-thirds of cardiovascular events to occur. Libby concludes, “To address the majority of cardiovascular events that still occur despite our most powerful existing therapies, we must combine lifestyle change and evaluate new pharmacological strategies that will move us toward the goal of eradicating cardiovascular disease in the future.”7 This has been highlighted in some of the trials that have compared high-dose versus low-dose statin or a potent statin versus a less potent statin. In clinical studies that have compared a statin versus placebo, we can see that there is a consistent benefit for statin therapy. This benefit occurs regardless, if the LDL cholesterol high, such as in the 4S Trial; borderline high, such as in the LIPID Trial and CARE Trial; or lower, such as in the Heart Protection Study. Across the board, statins provide benefit to individuals with established coronary heart disease, but they also provide benefit to individuals that are at risk, who have not yet had a CHD event, as was shown initially in the WOSCOPS Study and the AFCAPS/TexCAPS Study. Reference 4S Group. Lancet. 1994;344: LIPID Study Group. N Engl J Med. 1998;339: Sacks FM, et al. N Engl J Med. 1996;335: HPS Collaborative Group. Lancet. 2002;360:7-22. Shepherd J, et al. N Engl J Med. 1995;333: Downs JR, et al. JAMA. 1998;279: Libby PJ, et al. J Am Coll Cardiol, 2005:46: 4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/TexCAPS6 N 4444 9014 4159 20 536 6595 6605  LDL -35% -25% -28% -29% -26% -25% Secondary High Risk Primary 14S Group. Lancet. 1994;344: 2LIPID Study Group. N Engl J Med. 1998;339: 3Sacks FM et al. N Engl J Med. 1996;335: 4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333: 6 Downs JR et al. JAMA. 1998;279: 37

Potential Antiatherogenic Actions of HDL
Vasodilatory Activity Anti-inflammatory Activity Antithrombotic Activity HDL Antiapoptotic Activity Reverse Cholesterol Transport Cellular Cholesterol Efflux Anti-infectious Activity So all told, because of this very interesting protein cargo that HDL can carry, it confers a broad variety of functions including capacity to induce vasodilatation by stimulating endothelial cell function, nitric oxide production, prostacyclin production. It can even inhibit endothelial cell apoptosis, or programmed cell death, and promote endothelial cell repair. And because the HDL particle carries complements and other globulins, it also participates in immunity and combating infection. Other Antiatherogenic Actions of HDL. These include antiinflammatory activity, antioxidative activity, antiinfectious activity, antithrombotic activity, antiapoptotic activity, and vasodilatory activity. HDL also plays a role in endothelial repair.1,2 Antioxidative Activity Endothelial Repair Apo A-I Apo A-II Chapman MJ et al. Curr Med Res Opin. 2004;20: Assmann G et al. Annu Rev Med. 2003;53:

Should High-Density Lipoprotein Be a Target of Therapy?

Change in % stenosis per year On-treatment HDL-C (mg/dL)
Change in Percent Diameter Stenosis vs On-treatment HDL-C in QCA Trials 1.4 CCAIT 1.2 PLAC I LCAS 1 MARS MAAS Placebo 0.8 CCAIT MARS Statin* PLAC I 0.6 0.4 Change in % stenosis per year MAAS LCAS 0.2 -0.2 -0.4 -0.6 ASTEROID -0.8 -1 On-treatment HDL-C (mg/dL) *ASTEROID rosuvastatin MAAS simvastatin CCAIT lovastatin MARS lovastatin LCAS fluvastatin PLAC I pravastatin Ballantyne CM, Nicholls S et al. Circulation 2008; Online 40

Should High-Density Lipoproteins Be a Target of Therapy ?
ATP III Guidelines on HDL-C: “Current documentation of risk reduction through controlled clinical trials is not sufficient to warrant setting a specific goal value for raising HDL-C” (Grundy SM et al. Circulation. 2004;110: ) Failure of ACCORD, FIELD, AIM-HIGH and the experience with torcetrapib and dalcetrapib have raised doubts re: the value of raising HDL-C Still, The one best study of niacin effects on CVD (HPS-2/THRIVE) is ongoing—results early in 2013 Investigational CETP inhibitors greatly increase HDL-C and might be shown to reduce CVD—clinical trials ongoing, results after 2017 The ATP III Guidelines, as promulgated in , state the following: “Current documentation of risk reduction through controlled clinical trials is not sufficient to warrant setting a specific goal for raising HDL cholesterol.” There are no clinical trial that has yet been done that allows us to ascertain what the threshold for HDL-raising should be. For now, the rule of thumb is that, if someone’s HDL is low, then just try to raise it as much as you can. But this has been complicated by the findings of ACCORD, FIELD, and AIM-HIGH, as well as the discouraging results of the ILLUMINATE Trial with torcetrapib. But then there are also some recent encouraging clinical trial data from Next Generation Investigational CETP inhibitors, which don’t have the off-target toxicity of torcetrapib.

HDL-C Risk Factor vs Risk Marker?
Low HDL-C predicts high CVD Risk High HDL-C predicts anti-atherogenic effects: Anti-inflammatory Antioxidant Antithrombotic Pro-endothelial But clinical trials of HDL-C-raising agents so far have failed to prove CVD benefit—suggesting that HDL-C may be only a risk marker HDL -- is it a risk factor or is it simply a risk marker? Low HDL predicts high CVD risk in observational cohorts all over the world. A low HDL predicts increased risk for cardiovascular events, and a high HDL, with very few exceptions, portends protection from coronary artery disease and its various sequelae. High HDL cholesterol also predicts antiatherogenic effects; you can beneficially impact carotid intima media thickness as well as focal target plaques in coronary vessels. But clinical trials have not yet proven that HDL is a causal factor versus a biomarker of risk, or that raising HDL cholesterol reduces CVD risk. But there are some studies that have shown benefit to raising HDL. One clear example of this is the VA HIT Trial, where raising HDL was associated with a reduction in acute cardiovascular events in men with established coronary disease.

Lifestyle Modifications to Raise HDL-C Levels
Smoking Cessation HDL-C levels are lower in smokers (by 7%-20%), and return towards normal 1-2 months after smoking cessation Whole Food Plant Based Diet—dietary fiber blunts adverse carb effect Weight Reduction For every 3 kg (7 lb) of weight loss, HDL-C levels increase by 2-4%, but only after stabilization at new lower weight Exercise Aerobic exercise (40 min, 3-4 x weekly) may increase HDL- C by 5-10% So what are some lifestyle maneuvers that can help to raise HDL? Smoking cessation – smoking impacts HDL adversely in multiple wayys. including the fact that smoking promotes insulin resistance, which, of course, is associated with increased rates of HDL catabolism. If you get rid of the cigarette smoke, then HDL levels can increase quite substantially, even up to 20 to 25 percent, which is as good as the very best drugs that we currently have available. If you look at weight reduction, exercise, anything that relieves insulin resistance, then this is going to be associated with an increase in HDL. Clearly, lifestyle modification can impact HDL levels significantly. In summary, high-density lipoprotein cholesterol (HDL-C) levels are positively affected by certain lifestyle modifications, including weight reduction, smoking cessation, and exercise. For every 3 kg (7 lb) of weight loss, HDL-C levels increase 1 mg/dL. HDL-C levels in smokers are 7–20% lower than those in nonsmokers. HDL-C levels return to normal, however, within 30–60 days after smoking cessation. Aerobic exercise, such as running, increases HDL-C levels in a dose-dependent manner. Rössner S et al. Atherosclerosis. 1987;64: Wood PD et al. N Engl J Med. 1988;319: Ornish D et al. JAMA. 1998;280: Cullen P et al. Eur Heart J. 1998;19: Kokkinos PF et al. Arch Intern Med. 1995;155: Kodama S et al. Arch Intern Med. 2007;167:

Available Agents for HDL-C Raising
Agent HDL-C ↑ Primary Use Nicotinic acid 15-35% HDL ↑ Fibrates 5-20% TG ↓ Statins 5-15% LDL ↓ Prescr. Om-3* 2-10% TG ↓ Bile-acid resins* 2-5% LDL ↓ Ezetimibe* 1-3% LDL ↓ Pioglitazone* 5-20% Glucose ↓ Estrogens* 10-25% Hot flashes -blockers* 10-20% BPH Alcohol* 5-15% Social, etc. Effects of drugs on HDL-C levels A number of drugs are available for inducing HDL elevation. Among the very best for doing this are niacin, or nicotinic acid, as well as fibrates, followed by statins and other drugs. Niacin provides the greatest increase in HDL-C. *Lacking FDA-approved indication for HDL-raising. Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41: Insull W et al. Mayo Clin Proc. 2001;76: McKenney JM et al. Pharmacother. 2007;27:

Risk Reduction for CHD Events As a Function of Changes in TC, LDL-C, and HDL-C
PERCENT CHD EVENT CHANGE RATE These are observational data correlating the change in events in studies that made multiple changes in lipoprotein metabolism and it is not clear that any single change was the causative operator. For every 1 mg/dL that you drop LDL, you typically observe about a one-percent reduction in risk. But when it comes to HDL, for every 1 mg/dL that you raise HDL, on average, you drop risk about three percent in men, up to four percent in women. *4S, CARE, LIPID, WOSCOPS **HELSINKI, VA-HIT,AFCAPS/TexCAPS

Fibrate Evidence: Primary Prevention
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) 9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 years A fibrate does not provide significant additional benefit* in diabetics 11% RRR 9 5.9 6 5.2 CHD Death or Nonfatal MI (%) 3 P=0.16 The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study sought to assess the effect of fibrate therapy on cardiovascular disease events in patients with type 2 diabetes mellitus. A total of 9795 individuals with diabetes not on statin therapy at study entry were randomized to fenofibrate (200 mg daily) or placebo for 5 years. The primary outcome was a composite of coronary events, including coronary heart disease death or non-fatal myocardial infarction. There was no statistically significant reduction in the primary end point with fibrate therapy (5.2% vs. 5.9%, hazard ratio [HR] 0.89, 95% CI ; p=0.16). Treatment with fenofibrate, however, was associated with less albuminuria progression (p=0.002) and less retinopathy needing laser treatment (5.2% vs 3.6%, p=0.0003). Some of the disappointing results of the FIELD trial may have been due to a higher than expected use of statin therapy in the placebo group. Placebo Fenofibrate CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction *Unadjusted for concomitant statin use Source: Keech A et al. Lancet 2005;366: 46

ACCORD Lipid Study Results (NEJM 2010; 362: 1563-74)
5518 patients with type 2 DM treated with open label simvastatin randomly assigned to fenofibrate or placebo and followed for 4.7 years. Annual rate of primary outcome of nonfatal MI, stroke or CVD death 2.2% in fenofibrate group vs. 1.6% in placebo group (HR=0.91, p=0.33). Pre-specified subgroup analyses showed possible benefit in men vs. women and those with high triglycerides and low HDL-C. Results support statin therapy alone to reduce CVD risk in high risk type 2 DM patients.

Primary and Secondary Prevention
Fibrate Evidence: Primary and Secondary Prevention Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial 5,518 diabetic patients on statin therapy randomized to fenofibrate (160 mg) or placebo for 4.7 years On a background of statin therapy, a fibrate does not reduce CV events in diabetics 8% RRR 3 2.4 2.2 CV death, nonfatal stroke or nonfatal MI (%/year) 2 1 P=0.32 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. Placebo Fenofibrate CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: ACCORD study group. NEJM 2010;Epub ahead of print

Is Niacin Useful in Low HDL-C?

HATS: Percent Change in Stenosis
5.43 4.5 4.0 3.5 3.0 2.5 Change (%) 2.0 1.5 1.0 0.5 0.0 -0.5 Placebo Antioxidant Simvastatin/ Simvastatin / Vitamins* Niacin† Niacin/ Antioxidants‡ -1.0 *P = 0.16 for comparison with placebo; †P < 0.001; ‡P = HATS = HDL-Atherosclerosis Treatment Study. Adapted from Brown BG et al. N Engl J Med. 2001;345:

HATS: Patients Free of Events Patients Free of Events (%)
5.44 Simvastatin-niacin 100 97% 90 Patients Free of Events (%) All placebos 80 76% RR = 0.10 P = 0.03 70 1 2 3 Years HATS = HDL-Atherosclerosis Treatment Study. Adapted from Brown BG et al. N Engl J Med. 2001;345:

Meta-Analysis: Effects of Nicotinic Acid Pre-AIM-HIGH Trials: Major Coronary Events
Study Treatment n/N Control Peto OR 95% Cl ARBITER-6-HALTS 2/187 9/176 0.25 (0.08, 0.84) Guyton JR et al 1/676 1/272 0.35 (0.02, 7.56) AFREGS 0/71 1/72 0.14 (0.00, 6.92) ARBITER-2 2/87 2/80 0.92 (0.13, 6.65) HATS 1/38 5/38 0.24 (0.05, 1.26) UCSF_SCOR 0/48 1/49 0.14 (0.00, 6.96) STOCKHOLM 72/279 100/276 0.61 (0.43, 0.88) CLAS 1/94 5/94 0.25 (0.05, 1.29) CDP 287/1119 839/2789 0.81 (0.69, 0.94) Total Test for heterogeneity: P = 0.24, I2 = 23.0% Test for overall effect: P <0.0001 0.75 (0.65, 0.86) Subtotal excluding CDP 0.53 (0.38, 0.73) Log scale If you look at the risk for a major coronary event, risk – if you exclude the Coronary Drug Project – was reduced by about 47 percent. And ARBITER-6-HALTS, the Stockholm Heart Study, as well as the Coronary Drug Project all attained statistical significance. Overall, there is a trend, though, as we see that the confidence intervals cross one, and these studies did not hit statistical significance. Many of these trials were tests of drug combinations that included niacin. Bruckert E et al. Atherosclerosis. 2010;210:

AIM-HIGH Design Purpose: “Rigorous test of the HDL hypothesis…”
(not designed to be a test of niacin) Subjects: n=3414 men/women (85%/15%) w/ prior CVD event and HDL-C 35 (<42/53) LDL-C 74 (algorithm), TG 163 ( ) [median (range)] Randomized Therapy Extended-release niacin ( mg hs) vs “Placebo” (immediate-release niacin mg hs) Open-label titration/addition (keep LDL-C in mg/dL) Simvastatin 5-80 mg/d Ezetimibe 10 mg/d + extended release niacin ( mg) AIM-HIGH – everyone was looking forward to this trial, and it turned out to be negative. Actually, it was stopped prematurely because of futility based on an NIH analysis of the data. Basically, this study included about 3,500 men and women with a prior cardiovascular disease-related event, with a mean HDL of 35. The average LDL was 71, and the average non-HDL was about Patients were randomized to simvastatin, plus or minus ezetimibe, versus plus or minus niacin at 1500 to 2000 mg daily. The titration of LDL-C was done with simvastatin and then ezetimibe in both groups as needed. The titration of ER niacin was done only in the assigned group and the purpose was to reach maximum tolerated dose up to 2g/d. AIM-HIGH Investigators. N Engl J Med. 2001;365: AIM-HIGH Investigators. Am Heart J. 2011;161: e2.

AIM-HIGH — Results HDL-C at Baseline and Follow-up
In the trial, they saw about a 4-mg/dL increase in the niacin group compared to the group that did not receive niacin. Boden WE. N Engl J Med. epub 15 Nov 2011; doi /NEJMoa

AIM-HIGH — Results Primary Outcome
1o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization But as we see in the plots, looking at primary outcome, the curves for the two groups were virtually perfectly superimposable. And so with an average followup of just under three years, the study was discontinued due to futility. Still, we have the HPS2 THRIVE Study coming probably in the first quarter of next year, looking at 25,500 patients with a much broader range of baseline lipids with cardiovascular disease, also evaluating the impact of niacin therapy on top of statin therapy. So, the case is not closed yet. Boden WE. N Engl J Med. epub 15 Nov 2011; doi /NEJMoa

Fate of Niacin Beyond AIM-HIGH: HPS2-THRIVE : December 2012 Update
HPS2-THRIVE evaluated extended-release niacin/laropiprant plus statin therapy versus statin therapy alone in patients at high risk for cardiovascular events HPS2-THRIVE did not reach the primary endpoint to reduce coronary deaths, non-fatal heart attacks, strokes, or revascularizations This finding, supportive of AIM-HIGH, suggests that niacin may not provide additional benefit to reduce CVD risk when patients are well-treated with statins

Emerging HDL-C Therapies
CETP Antagonism

Role of CETP in Atherosclerosis
LIVER PERIPHERAL TISSUE CE TG Bile Foam cells RCT HDL ABC-A1 VLDL LDL PLASMA LDL-R ABC-G1 Free cholesterol CETP Athero- sclerosis So what are some emerging HDL therapies? The hot buttons here are these CETP inhibitors, and there is a number of them currently in development – three. And what does a CETP inhibitor do, and how does it impact HDL levels? CETP inhibition would preserve HDL levels in serum, keep cholesterol ester levels higher in the HDL compartment, and reduce the loading of Apo B particles with cholesterol ester, but it would also decrease rates of indirect reverse cholesterol transport. CETP inhibitors do show promise because they raise HDL quite substantially. They also provide incremental LDL reduction. Key points HDL plays an essential anti-atherogenic role in the transport of cholesterol from extrahepatic tissues to the liver. CETP transfers cholesteryl esters from HDL to pro-atherogenic LDL and VLDL particles. Inhibition of CETP may enhance the anti-atherogenic effects of HDL, by reducing the transfer of cholesteryl esters from HDL to pro-atherogenic VLDL or LDL particles. Human CETP deficiency is usually associated with marked ↑ in HDL-C CETP activity is inversely correlated with plasma HDL-C Decreasing CETP activity has consistently inhibited atherosclerosis in animal models Barter PJ et al. Arterioscler Thromb Vasc Biol. 2003;23: Contacos C et al. Atherosclerosis. 1998;141:87-98. Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28:

CETP Inhibitors: 2 Down, 2 Remain
↑HDL-C ~80% ~80% ~138% ~30% Evacetrapib ↑CVD (25%) but OK HDL function (off-target eff.?) *No ↓CVD, but OK HDL function, +/- anti athero? CETP Barter et al. N Engl J Med. 2007;357(13): *Dalcetrapib development stopped May 7, 2012 due to lack of efficacy in the Dal-Outcomes CVD endpoint trial. Qiu X et al. Nat Struct Mol Biol. 2007;14(2):

Lipid Effects of CETP Inhibitors/Modulators % Change from Baseline
CETP Agent Dose (mg/day) HDL-C (%) LDL-C (%) TG (%) Torcetrapib 60 61 -24 -9 Anacetrapib 100 138 -40 -7 Evacetrapib 500 129 -36 -11 Dalcetrapib 600 31 -2 -3 Dalcetrapib raises HDL about 31 percent, anacetrapib about 138 percent, evacetrapib about 129 percent, and they also provide some degree of incremental LDL reduction; although, dalcetrapib appears to be the exception, as it is really good at raising HDL but appears relatively neutral on LDL and triglyceride. Adapted from Cannon C et al. JAMA. 2011;306: Nicholls SJ et al. JAMA. 2011;306:

Torcetrapib “Beneficial” Effects on Lipoproteins
HDL-C LDL-C +42% +49% +55% -20% -18% -1% +1% If you look at the torcetrapib, everything moved in the right direction. HDL zoomed up, and LDL dropped incrementally as a function of dose Placebo 60 mg 90 mg 120 mg Is the toxicity of torcetrapib related to the mechanism or the molecule? Barter PJ et al. N Engl J Med. 2007;357:

Days After Randomization
Torcetrapib: Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality Atorvastatin only HR = 1.25 P = Patients Without Event (%) Torcetrapib plus atorvastatin Days After Randomization Is the toxicity of torcetrapib related to the mechanism or the molecule? Barter PJ et al. N Engl J Med. 2007;357:

Torcetrapib Caused Off-target Hyperaldosteronism
Torcetrapib arm of ILLUMINATE trial showed significant:1 ↑ Systolic Blood Pressure: Mean ↑5.4 mmHg >15 mmHg ↑ SBP: 19.5% torcetrapib arm (vs 9.4% placebo arm, P<0.001) ↓ serum potassium ↑ serum bicarbonate ↑ serum sodium ↑ serum aldosterone Inverse relationship of CVD and on-Rx-HDL-C preserved Conclusion: ↑ CVD in ILLUMINATE likely due to off-target actions of torcetrapib, not related to CETP inhibition1,2 Torcetrapib certainly influenced lipoproteins in a good way because HDL went up and LDL went down, but blood pressure also went up significantly. And in the torcetrapib arm of ILLUMINATE, up to 20 percent of patients had a 15-millimeter mercury elevation in systolic blood pressure or worse. They also had severe electrolyte disturbances because the torcetrapib stimulated aldosterone synthase activity, which increased serum aldosterone, and potassium levels dropped, and serum sodium and bicarbonate levels rose. Key points A consistent finding of the clinical trials with torcetrapib was the occurrence of adverse effects not related to its effect on CETP. Instead, the torcetrapib molecule has off-target effects, especially related to blood pressure control; an effect that is likely related to an increase in serum aldosterone. This slide summarizes the off-target effects of torcetrapib in the large outcomes trial; evidence for the off-target negative effects of torcetrapib can be seen in the electrolyte disturbances. 1. Barter PJ et al. N Engl J Med. 2007;357: 2. Rosenson RS. Curr Athero Rep. 2008;10:

dal-OUTCOMES Results: Isolated ↑HDL-C
HDL Cholesterol (mg/dL) No. at risk Placebo Dalcetrapib There is a well-established linear relationship between LDL cholesterol and cardiovascular events, especially when we look at the statin trials. If you plot all the statin trials – placebo group and the treatment group – we find a very linear relationship between LDL cholesterol values and cardiovascular events. And the actual data supports the fact that it is the on-treatment level that predicts the outcome even better than the dose of the statin utilized when it comes to cardiovascular risk reduction. LDL Cholesterol (mg/dL) Schwartz GG et al. N Engl J Med Nov 5. [Epub ahead of print]. Months No. at risk Placebo Dalcetrapib

Cumulative Incidence of Primary Outcome (% of patients)
dal-OUTCOMES Results: No ↓CVD Cumulative Incidence of Primary Outcome (% of patients) There is a well-established linear relationship between LDL cholesterol and cardiovascular events, especially when we look at the statin trials. If you plot all the statin trials – placebo group and the treatment group – we find a very linear relationship between LDL cholesterol values and cardiovascular events. And the actual data supports the fact that it is the on-treatment level that predicts the outcome even better than the dose of the statin utilized when it comes to cardiovascular risk reduction. Year No. at risk Placebo Dalcetrapib Schwartz GG et al. N Engl J Med Nov 5. [Epub ahead of print].

Annualized Event Rate (%)
dal-OUTCOMES Results: HDL STILL Functional Annualized Event Rate (%) There is a well-established linear relationship between LDL cholesterol and cardiovascular events, especially when we look at the statin trials. If you plot all the statin trials – placebo group and the treatment group – we find a very linear relationship between LDL cholesterol values and cardiovascular events. And the actual data supports the fact that it is the on-treatment level that predicts the outcome even better than the dose of the statin utilized when it comes to cardiovascular risk reduction. Change in HDL Cholesterol (mg/dL) from Baseline to Month 1, According to Quintile Schwartz GG et al. N Engl J Med Nov 5. [Epub ahead of print].

Anacetrapib Effects on LDL-C and HDL-C
20 40 60 80 100 20 40 60 80 100 120 -39.8% (P<0.001) +138.1% (P<0.001) LDL-C (mg/dL) (SE) HDL-C (mg/dL) (SE) Anacetrapib Placebo Anacetrapib Placebo If you look at anacetrapib, in this study done by Chris Cannon and the TIMI Group, you will see that there is incremental LDL reduction at about 40 percent and a 138-percent elevation in HDL cholesterol relative to placebo. The point estimates are for wk 24 Baseline 6 12 18 24 30 46 62 76 Baseline 6 12 18 24 30 46 62 76 Study Week Study Week Anacetrapib n = 804 771 716 687 646 604 568 540 Anacetrapib n = 776 757 718 687 647 607 572 543 Placebo n = 803 759 741 743 735 711 691 666 Placebo n = 766 761 741 744 736 711 691 666 Cannon CP et al. N Engl J Med. 2010;363:

Revisiting the HDL Hypothesis Where do we go Next?
Residual CVD risk exists despite intense statin monotherapy Low HDL-C predicts high CVD risk; high HDL-C is protective Existing HDL raising therapies have inconsistent effects Clinical trials have not yet answered the following: Is HDL a causal factor or a biomarker of risk? Does raising HDL-C reduce CVD risk? Investigational drugs to raise HDL-C and reduce CVD risk Continued need for multifactorial approaches to reduce CVD risk

Current Investigational Approaches to Reduce Residual CVD Risk via Enhanced HDL, etc.
Additional CETP inhibitors: anacetrapib, evacetrapib Apolipoprotein A1 (Apo A1) Milano; Apo A1 agonist Delipidated HDL; rHDL Selective LXRβ (liver X receptor) agonist DMHCA; GW 3965 PPAR (peroxisome proliferator-activated receptor α/γ agonist aleglitazar, muraglitazar, tesaglitazar DPP-4 (dipeptidyl peptidase-4) antagonist alogliptin, linagliptin, saxagliptin, sitagliptin MTP (microsomal transport protein) antagonist

Lp-PLA2 and vascular disease
LpPLA2 Studies Collaboration (2010) Lancet 375;

Novel anti-atherosclerotic agents Darapladib in animal models and clinical trials
Effects of Lp-PLA2 inhibition by darapladib in diabetic, hypercholesterolemic pigs STABILITY Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Estimated enrolment 15,500 Darapladib vs placebo in well treated patients with CHD plus other risk. 1ary endpoint major coronary event SOLID – TIMI52 Stabilization of plaques using darapladib. Incidence of major coronary events in patients with ACS Darapladib 160 mg vs placebo started within 30 days of index ACS event. Wilensky et al (2008) Nature Medicine (in press)

NCEP ATP III: Evaluation— Major Risk Factors for CAD
Age (men 45 y; women 55 y) Cigarette smoking Hypertension (BP 140/90 mm Hg or antihypertensive medication) HDL-C <40 mg/dL Family history of premature CAD <55 y in first-degree male relative <65 y in first-degree female relative The major risk factors for CAD are Age over 45 for men and over 55 for women Smoking Hypertension (BP 140/90 mm Hg or antihypertensive medication) HDL-C <40 mg/dL Family history of premature CAD Before the age of 55 in a first-degree male relative Before the age of 65 in a first-degree female relative Although it is a well-established risk factor, LDL-C is not included because it is recognized to be modified by other major risk factors. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Executive Summary of 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). JAMA. 2001;285:

Revised ATP III (AHA/NHLBI) Metabolic Syndrome Definition 2005
<40 mg/dL <50 mg/dL or Rx for ↓ HDL Men Women >102 cm (>40 in) >88 cm (>35 in) 100 mg/dL or Rx for ↑ glucose Fasting glucose 130/85 mm Hg or on HTN Rx Blood pressure HDL-C 150 mg/dL or Rx for ↑ TG TG Abdominal obesity† (Waist circumference‡) Defining Level Risk Factor *Diagnosis is established when 3 of these risk factors are present. †Abdominal obesity is more highly correlated with metabolic risk factors than is BMI ‡Some men develop metabolic risk factors when circumference is only marginally increased. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: ; Updated AHA/NHLBI Statement Oct 18, 2005: Grundy et al. Circulation 2005; 112 (epub).

NCEP ATP III: Evaluation— Need for Framingham Calculation
No >20% CAD or CAD risk equivalent Yes 0%-10% 2 RF <10% 1 RF Need for Framingham Calculation 10-Year Risk for CAD Risk Profile 10%-20% NCEP ATP III guidelines define 3 categories of risk, according to the number of risk factors and evidence of CAD or CAD risk equivalent. For individuals with 0 or 1 risk factor, the 10-year risk for CAD is <10%, and there is no need to calculate the absolute risk. For individuals with 2 or more risk factors, the 10-year risk for CAD varies from <10% to 10%-20%, and the absolute risk needs to be calculated to determine the appropriate management. For individuals with established CAD or a CAD risk equivalent, the 10-year risk of a coronary event is >20%, and there is no need to calculate the absolute risk. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Executive Summary of 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). JAMA. 2001;285:

NCEP ATP III: Evaluation— CAD Risk Equivalents
Diabetes Atherosclerotic disease Peripheral artery disease Abdominal aortic aneurysm Symptomatic carotid artery disease CAD 10-year risk >20% NCEP ATP III guidelines recognize the presence of CAD risk equivalents (eg, diabetes, atherosclerotic disease in other vascular beds, combination of several risk factors) that are associated with a 10-year risk equivalent to that of established CAD (>20%). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Executive Summary of 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). JAMA. 2001;285:

Assessing CHD Risk in Men
ATP III Framingham Risk Scoring Assessing CHD Risk in Men Step 1: Age Years Points Systolic BP Points Points (mm Hg) if Untreated if Treated < ³ Step 4: Systolic Blood Pressure Age Total cholesterol HDL-cholesterol Systolic blood pressure Smoking status Point total Step 6: Adding Up the Points Step 7: CHD Risk Point Total 10-Year Risk Point Total 10-Year Risk <0 <1% 11 8% 0 1% 12 10% 1 1% 13 12% 2 1% 14 16% 3 1% 15 20% 4 1% 16 25% 5 2% ³17 ³30% 6 2% 7 3% 8 4% 9 5% 10 6% TC Points at Points at Points at Points at Points at (mg/dL) Age Age Age Age Age 70-79 < ³ Step 2: Total Cholesterol HDL-C (mg/dL) Points ³60 -1 <40 2 Step 3: HDL-Cholesterol Step 5: Smoking Status Points at Points at Points at Points at Points at Age Age Age Age Age 70-79 Nonsmoker Smoker Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: © 2001, Professional Postgraduate Services®

Assessing CHD Risk in Women
ATP III Framingham Risk Scoring Assessing CHD Risk in Women Step 1: Age Years Points Systolic BP Points Points (mm Hg) if Untreated if Treated < ³ Step 4: Systolic Blood Pressure Age Total cholesterol HDL-cholesterol Systolic blood pressure Smoking status Point total Step 6: Adding Up the Points Step 7: CHD Risk Point Total 10-Year Risk Point Total 10-Year Risk <9 <1% 20 11% 9 1% 21 14% 10 1% 22 17% 11 1% 23 22% 12 1% 24 27% 13 2% ³25 ³30% 14 2% 15 3% 16 4% 17 5% 18 6% 19 8% Step 2: Total Cholesterol TC Points at Points at Points at Points at Points at (mg/dL) Age Age Age Age Age 70-79 < ³ HDL-C (mg/dL) Points ³60 -1 <40 2 Step 3: HDL-Cholesterol Step 5: Smoking Status Points at Points at Points at Points at Points at Age Age Age Age Age 70-79 Nonsmoker Smoker Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: © 2001, Professional Postgraduate Services®

Total Cholesterol:HDL Ratio
hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI Relative Risk A critical clinical question has been whether or not CRP levels add to information based upon cholesterol evaluation. As shown here, high sensitivity evaluation for CRP (hs-CRP) clearly adds to the predictive value of the total to HDL cholesterol ratio. As also shown, risk is high for those with elevated levels of CRP but average cholesterol values. Such patients, however, are largely missed by current screening protocols. hs-CRP Total Cholesterol:HDL Ratio Ridker et al, Circulation. 1998;97:2007–2011.

JUPITER Why Consider Statins for Low LDL, high hsCRP Patients?
AFCAPS/TexCAPS Low LDL Subgroups Low LDL, Low hsCRP Low LDL, High hsCRP Low LDL, Low hsCRP Low LDL, High hsCRP [A] [B] 0.5 1.0 2.0 0.5 1.0 2.0 RR Statin Effective Statin Not Effective Statin Effective Statin Not Effective However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. Ridker et al, New Engl J Med 2001;344:

JUPITER Trial Design JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP MI Stroke Unstable Angina CVD Death CABG/PTCA Rosuvastatin 20 mg (N=8901) No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L Placebo (N=8901) 4-week run-in Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela Ridker et al, Circulation 2003;108:

JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Ridker et al NEJM 2008 HR 0.56, 95% CI P < Placebo 251 / 8901 0.08 Number Needed to Treat (NNT5) = 25 - 44 % 0.06 Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 0.00 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

JUPITER population – high CRP (>2mg/l), low LDL
Dual Target Analysis: LDL-C <70 mg/dL, hsCRP <2 mg/L 0.08 placebo HR 1.0 (referent) P <0.0001 0.06 LDL >70 mg/dL and / or hsCRP >2 mg/L HR 0.64 ( ) 0.04 Cumulative Incidence LDL <70 mg/dL and hsCRP <2 mg/L HR 0.35 ( ) 0.02 0.00 1 2 3 4 Follow-up (years) Number at Risk rosuvastatin 7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145 placebo 7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168 Ridker PM et al. Lancet 2009;373:1175–1182

NCEP ATP III Guidelines: Treatment
LDL - C Level to Initiate Drug Therapy (mg/dL) 190 160 130 <160 <130 <100 LDL - C Goal (mg/dL) 160 130 100 LDL - C Level to Initiate TLC (mg/dL) Risk Category 1 RF (10-year risk 0%-10%) 2 RFs (10-year risk 10%-20%) The NCEP ATP III guidelines recommend the use of therapeutic lifestyle changes (TLC) and pharmacologic therapy according to the LDL-C goals and calculated risk. In individuals with an LDL-C goal of <160 mg/dL, initiation of TLC and pharmacologic therapy is recommended at LDL-C levels of 160 mg/dL and 190 mg/dL, respectively. In individuals with an LDL-C goal of <130 mg/dL, initiation of TLC is recommended at LDL-C level of 130 mg/dL, regardless of their 10-year risk of developing CAD. Initiation of pharmacologic therapy is recommended at LDL-C level of 160 mg/dL in patients with a 10-year risk of <10% and at LDL-C level of 130 mg/dL in those with a 10-year risk of 10%-20%. In individuals with an LDL-C goal of <100 mg/dL, initiation of TLC and pharmacologic therapy is recommended at LDL-C levels of 100 mg/dL and 130 mg/dL, respectively. CAD or CAD risk equivalent Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Executive Summary of 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). JAMA. 2001;285:

Statins in ACS - Guidelines
Who - Initiate therapy regardless of baseline LDL. When – Pre-discharge; but no difference in benefit when initiated immediately or days post event (ESC <4 days). What – Evidence base is for high dose statin (but not 80mg simvastatin). Goal - <70 mg/dl (2.0 mmol/l) LDL cholesterol. ACC/ AHA 2007 in JACC (2008) 51; ESC 2007 in Eur Heart J (2007) 28;

Lipid Management Goal: Persons with Pre-existing CHD
LDL-C should be less than 100 mg/dL Further reduction to LDL-C to < 70 mg/dL is reasonable I IIa IIb III If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL* *Non-HDL-C = total cholesterol minus HDL-C

NCEP ATP III: Setting Goals— Secondary–Non-HDL-C
(Patients With TG 200) Risk Category Non–HDL-C Goal (mg/dL) 1 RF <190 2 RFs (CAD risk 20%) <160 CAD or CAD risk equivalent <130 (CAD risk >20%) In patients with elevated TG (200 mg/dL), cholesterol content of atherogenic remnant lipoprotein particles (chylomicron remnant, VLDL remnant) may be increased, and LDL-C alone may not be an adequate risk predictor. In these individuals, measurement of non–HDL-C (calculated by subtracting HDL-C from TC) is recommended, and its reduction is defined as a secondary therapeutic goal. Non–HDL-C goals are set at 30 mg/dL above the LDL-C goal in each risk category. For individuals with 0 or 1 risk factor: <190 mg/dL For individuals with 2 risk factors and a 10-year risk of 0%-20%: <160 mg/dL For individuals with established CAD or a CAD risk equivalent: <130 mg/dL Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Executive Summary of 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). JAMA. 2001;285:

ATP III Classification of Other Lipoprotein Levels
Total Cholesterol HDL-Cholesterol Level (mg/dl) Classification <200 Desirable Borderline High >240 High Level (mg/dl) Classification >40 Minimum goal* 40-50 Desired goal* >50 High Triglyceride Level (mg/dl) Classification <150 Normal Borderline High High >500 Very High The NCEP ATP III guidelines identify LDL cholesterol as the primary target for lipid intervention, but recognize total cholesterol, HDL cholesterol, and triglycerides as important factors. HDL=High density lipoprotein *These goals apply to men. For women, the minimum goal is >50 mg/dL Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285: 87 87

NCEP ATP III Guidelines: Treatment
Therapeutic Lifestyle Change (TLC) Improve diet Weight reduction Physical activity Pharmacologic Treatment Statins (HMG-CoA reductase inhibitors) Fibrates Niacin Bile acid sequestrants NCEP ATP III guidelines recommend therapeutic lifestyle changes (TLC) as an essential component of lipid-lowering. Diet Reduced intake of saturated fat (<7% of total calories) Reduced intake of cholesterol (<200 mg/d) Use of plant stanols/sterols Use of soluble fiber Weight reduction Increased physical activity Patients at high risk are likely to require both TLC and pharmacologic therapy. Statins Fibrates Niacin Bile acid sequestrants These agents target different aspects of lipid metabolism and have been shown to reduce the risk of CAD. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Executive Summary of 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). JAMA. 2001;285:

Lipid Management Recommendations
For all patients Start dietary therapy (<7% of total calories as saturated fat and <200 mg/d cholesterol) Adding plant stanol/sterols (2 gm/day) and viscous fiber (>10 mg/day) will further lower LDL Promote daily physical activity and weight management. Encourage increased consumption of omega-3 fatty acids in fish or 1 g/day omega-3 fatty acids in capsule form for risk reduction. I IIa IIb III

Therapeutic Lifestyle Changes Nutrient Composition of TLC Diet
Nutrient Recommended Intake Saturated fat Less than 7% of total calories Polyunsaturated fat Up to 10% of total calories Monounsaturated fat Up to 20% of total calories Total fat 25–35% of total calories Carbohydrate 50–60% of total calories Fiber 20–30 grams per day Protein Approximately 15% of total calories Cholesterol Less than 200 mg/day Total calories (energy) Balance energy intake and expenditure to maintain desirable body weight

Possible Benefits From Other Therapies
5.10 Therapy Result Soluble fiber in diet (2–8 g/d) (oat bran, fruit, and vegetables) Soy protein (20–30 g/d) Stanol esters (1.5–4 g/d) (inhibit cholesterol absorption) Fish oils (3–9 g/d) (n-3 fatty acids)  LDL-C 1% to 10%  LDL-C 5% to 7%  LDL-C 10% to 15%  Triglycerides 25% to 35% Jones PJ. Curr Atheroscler Rep. 1999;1: Lichtenstein AH. Curr Atheroscler Rep. 1999;1: Rambjor GS et al. Lipids. 1996;31:S45-S49. Ripsin CM et al. JAMA. 1992;267:

Dietary Adjuncts TLC for patients with LDL-C = 160 Dietary Component
LDL-C  (mg/dL) Low saturated fat/dietary cholesterol –12 Viscous fiber (10–25 g/d) –8 Plant stanols/sterols (2 g/d) –16 Total –36 mg/dl Dietary adjuncts This slide shows that in a hypothetical patient with an LDL-C of 160 mg/dL, average reductions in LDL-C obtained by a diet lower in saturated fat and dietary cholesterol and the addition of viscous fiber and plant stanol/sterol esters could reduce LDL-C to <130 mg/dL. This is the goal for many patients with multiple risk factors and may obviate the need for cholesterol-lowering drug therapy or an increase in dosage of cholesterol-lowering drug therapy. References: Walden CE, Retzlaff BM, Buck BL, McCann BS, Knopp RH. Lipoprotein lipid response to the National Cholesterol Education Program Step II diet by hypercholesterolemic and combined hyperlipidemic women and men. Arterioscler Thromb Vasc Biol 1997;17: Jenkins DJ, Kendall CW, Axelsen M, Augustin LS, Vuksan V. Viscous and nonviscous fibres, nonabsorbable and low glycaemic index carbohydrates, blood lipids and coronary heart disease. Curr Opin Lipidol 2000;11:49-56. Cato N. Stanol meta-analysis. Personal communication, 2000. Walden CE et al. Arterioscler Thromb Vasc Biol 1997;17: Jenkins DJ et al. Curr Opin Lipidol 2000;11:49-56. Cato N. Stanol meta-analysis. Personal communication, 2000.

Hospital Specialty_FINAL ATS
4/8/2017 4:57 AM THE REAL NIGHTMARE Moderate physical activity at least minutes 5 days a week or longer will help to raise HDL-C, lower total and LDL-C, lower TG, lower glucose, insulin, and blood pressure levels. 95

Effect of Lipid-modifying Therapies
Therapy TC LDL HDL TG Patient tolerability Bile acid sequestrants ¯ 7-10% ¯ 10-18% 3% Neutral or Poor Nicotinic acid ¯ 10-20% 14-35% ¯ 30-70% Poor to reasonable Fibrates (gemfibrozil) ¯ 19% ¯ 4-21% 11-13% ¯ 30% Good Statins* ¯ 19-37% ¯ 25-50% 4-12% ¯ 14-29% Ezetimibe ¯ 13% ¯ 18% 1% ¯ 9% Lipid-modifying therapies include HMG CoA reductase inhibitors (statins), fibrates, bile acid sequestrants (resins), nicotinic acid and its derivatives, and probucol. Statins are highly effective in lowering LDL-cholesterol and have a good tolerability profile.1-3 Data presented in this slide does not include rosuvastatin. Bile acid sequestrants are potent cholesterol-modifying agents. Adverse events such as gastrointestinal bloating, nausea and constipation limit compliance to the bile acid sequestrants.1,2 Nicotinic acid, a B-complex vitamin, is effective at reducing both LDL cholesterol and triglyceride concentrations, and increasing HDL cholesterol levels. To be effective, it must be given in pharmacologic doses. The value of nicotinic acid has been limited by the incidence of adverse events, which include flushing, skin problems, gastrointestinal distress, liver toxicity, hyperglycaemia and hyperuricemia.1,2 Fibrates are effective triglyceride-lowering and HDL-raising drugs. However, in the majority of patients they are only moderately successful in reducing LDL-cholesterol.1,2 Probucol is not available in most countries. It has only a modest LDL-cholesterol-lowering effect, and there is no evidence that it reduces CHD risk and there are limited long-term tolerability data.1,2 Ezetimibe is the first of a novel class of selective cholesterol-absorption inhibitors. Ezetimibe may be useful in patients who are intolerant to other lipid-modifying therapies, and in combination with a statin in patients who are intolerant to large doses of statins or need further reductions in LDL cholesterol despite maximum doses of a statin.4 References 1. Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391. 2. National Cholesterol Education Program. Circulation 1994;98(3):1333–1445. 3. Knopp RH. N Engl J Med 1999;341:498–511. 4. Gupta EK, Ito MK. Heart Dis 2002;4:399–409. TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin. Questran® Prescribing Information, Colestid ® Prescribing Information, WelChol ® Prescribing information, Niaspan ® Prescribing Information, Lopid ® Prescribing Information, TriCor ® Prescribing Information, Lipitor ® Prescribing Information, Zocor ® Prescribing Information, Mevaco ® r Prescribing Information, Lescol ® Prescribing Information, Pravacol ® Prescribing Information; Zetia ® Prescribing Information.

When LDL-lowering drug therapy is employed in high-risk or moderately high risk patients, intensity of therapy should be sufficient to achieve a 30–40% reduction in LDL-C levels. Summary (I) In patients at high or moderately risk, therapeutic lifestyle change is an integral part of risk reduction. If an LDL-C–lowering drug is used, the intensity of therapy should achieve an additional LDL-C reduction of at least 30–40% beyond diet.

Effect of Statin Therapy on LDL-C Levels: “The Rule of 6”
Key point: In general, Rule of 6: Each doubling of the dose of a statin drug produces approximately a 6% decrease in LDL-C. The potency of the statin drugs varies, with fluvastatin being the least potent and atorvastatin the most potent of the currently available compounds.8 The effect of the statins on LDL-C is dose related. The recommended starting dose of each statin drug results in a mean reduction in LDL-C of approximately 19% to 37%. Thereafter, a doubling of the dose of the statin drug lowers LDL-C approximately 6%. Titration to the maximum approved dose produces a mean reduction of approximately 31% to 51%.8 Statins are indicated as an adjunct to diet to reduce elevated total cholesterol, LDL-C, apolipoprotein B, and triglyceride levels and to increase high-density-lipoprotein (HDL)-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and combined hyperlipidemia (Fredrickson types IIa and IIb) after a trial of diet and other nondrug therapy has proved inadequate. Illingworth DR. Med Clin North Am. 2000;84:23-42.

Percentage Change From Baseline in LDL-C at Week 6 by Dose (ITT)1,2
10 mg 20 mg 40 mg 80 mg –60 –50 –40 –30 –20 –10 Rosuvastatin Atorvastatin Simvastatin Pravastatin Mean Percent Change From Baseline in LDL-C (SE) This slide shows the percentage change from baseline in LDL-C at week 6 by drug and dose range comparison. Rosuvastatin mg reduced LDL-C significantly more than atorvastatin across the dose range of mg (P<.002) aligning the maximum doses of each drug.2 Rosuvastatin 10 mg resulted in a statistically significant greater percent reduction in LDL-C compared with atorvastatin 10 mg; simvastatin 10 mg, 20 mg, or 40 mg; or pravastatin 10 mg, 20 mg, or 40 mg (P< 0.002). Rosuvastatin 20 mg treatment resulted in a statistically significant greater percent reduction in LDL-C compared with atorvastatin 20 mg or 40 mg (P<0.002); pravastatin 20 mg or 40 mg, or simvastatin 20 mg, 40 mg, or 80 mg (P< 0.002). Rosuvastatin 40 mg treatment resulted in statistically significantly greater percent reductions in LDL-C compared with atorvastatin 40 mg, pravastatin 40 mg, or simvastatin 40 mg or 80 mg (P< 0.002). Reference Jones PH, Davidson MH, Stein EA, et al. Comparison of the Efficacy and Safety of Rosuvastatin Versus Atorvastatin, Simvastatin, and Pravastatin Across Doses (STELLAR Trial) Am. J. Cardiology 2003; 93: 2. Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE. * ** † *P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg **P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg † P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE. /03

Doses of Statins Required to Attain
30-40% Reduction of LDL-C Dose, mg/d LDL Reduction, % Atorvastatin 10 39 Lovastatin 40 31 Pravastatin 34 Simvastatin 20-40 35-41 Fluvastatin 40-80 25-35 Rosuvastatin 5-10 39-45 At their starting dosages, all of the currently available statins reduce levels of LDL cholesterol and triglycerides, and increase levels of HDL cholesterol. Rosuvastatin is the most potent at LDL lowering. Reference Product Data Sheets Grundy et al. Circulation ;110:

74,102 subjects in 35 randomized clinical trials with statins
HMG-CoA Reductase Inhibitor: Adverse Effects 74,102 subjects in 35 randomized clinical trials with statins 1.4% incidence of elevated hepatic transaminases (1.1% incidence in control arm) Dose-dependent phenomenon that is usually reversible Hepatocyte 15.4% incidence of myalgias* (18.7% incidence in control arm) 0.9% incidence of myositis (0.4% incidence in control arm) 0.2% incidence of rhabdomyolysis (0.1% incidence in control arm) The incidence of very high transaminases or myositis is relatively low with statin therapy. Skeletal myocyte *The rate of myalgias leading to discontinuation of atorvastatin in the TNT trial was 4.8% and 4.7% in the 80 mg and 10 mg arms, respectively. Source: Kashani A et al. Circulation 2006;114: 101

Why combination therapy?
Few patients achieve LDL-C goal on monotherapy Uptitration of dosage is rare LDL-C goals are getting more aggressive High-dose statins increase risk of side effects Can address mixed dyslipidemia (e.g., few pts achieve adequate control of HDL-C and triglycerides on monotherapy) Combinations of lipid-lowering agents may help patients achieve their LDL cholesterol goals, which happens infrequently on statin monotherapy, especially for patients who have the most aggressive goals (those with CHD or CHD risk equivalents). Studies have shown that few physicians uptitrate statin dosages as necessary to achieve LDL cholesterol goals. Furthermore, using high does of statins increases the risk of muscle symptoms and liver enzyme abnormalities. Finally, use of combinations of drugs with different mechanisms may address lipid abnormalities in patients with mixed dyslipidemias.

Options for Patients who Fail to Reach LDL-C Goal on Statin Monotherapy
Addition of: Niacin Bile acid sequestrant Cholesterol absorption inhibitor

Pharmacologic Therapy: Niacin
Reduces HDL catabolism and VLDL production Primarily used to treat low HDL-C (15%-35%) and elevated TG (20%-50% ) LDL-C  5%-25% Side effects Hepatotoxicity, hyperglycemia, hyperuricemia, upper GI distress, flushing, itching Contraindicated in patients with liver disease, gout, peptic ulcer Niacin reduces hepatic HDL catabolism and VLDL production. Niacin is primarily used to treat low HDL-C and elevated TG. HDL-C is increased by 15%-35%. TG is reduced by 20%-50%. Niacin also reduces LDL-C by 5%-25%. Side effects of niacin include hepatotoxicity, hyperglycemia, hyperuricemia, upper gastrointestinal distress, and flushing. Niacin is contraindicated in patients with liver disease, gout, or peptic ulcer. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Executive Summary of 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). JAMA. 2001;285:

Mean change from Baseline
Nicotinic Acid Evidence: Effect on Lipid Parameters 30% -50 -40 -30 -20 -10 10 20 30 30% 26% HDL-C 22% 15% 10% –9% Mean change from Baseline –14% –5% –17% –21% –22% –11% LDL-C –28% This slide shows representative data with extended release niacin. Niacin is the most effective medication for increasing levels of HDL-C; however, it also lowers levels of LDL-C and triglycerides. –35% TG –39% –44% Dose (mg) 500 1000 1500 2000 2500 3000 HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride Source: Goldberg A et al. Am J Cardiol 2000;85: 105 105

Bile Acid Sequestrants
Major actions Reduce LDL-C 15%-30% Raise HDL-C 3%-5% May increase TG Side effects GI distress/constipation Decreased absorption of other drugs (1st generation) Contraindications Dysbetalipoproteinemia Elevated TG (especially >400 mg/dL) Bile acid sequestrants reduce LDL-C by 15%-30%, raise HDL-C by 3%-5%, but may increase TG in patients with hypertriglyceridemia. Side effects associated with bile acid sequestrants include gastrointestinal distress or constipation, which may often lead to decreased compliance. Additionally, first-generation agents (such as cholestyramine) reduce absorption of other drugs. Bile acid sequestrants are contraindicated in patients with dysbetalipoproteinemia and in individuals with elevated TG (particularly those with TG >400 mg/dL).

New Bile Acid Sequestrant: Colesevelam
Lower dose for effect Fewer GI complaints than with other bile acid sequestrants Reduces absorption of -carotene Requires 4-6 tablets/day A bile acid sequestrant introduced more recently, colesevelam, is effective at lower doses and is associated with fewer GI disturbances than previous agents in this class. Colesevelam has been reported to reduce intestinal absorption of b-carotene. Colesevelam regimen consists of 4-6 large tablets per day, which may decrease compliance. Davidson et al. Expert Opin Investig Drugs. 2000;9:2663. Davidson MH, Dicklin MR, Maki KC, Kleinpell RM. Colesevelam hydrochloride: a non-absorbed, polymeric, cholesterol-lowering agent. Expert Opin Investig Drugs. 2000;9:

Colesevelam Monotherapy: Efficacy
LDL-C HDL-C TG † % Change from baseline at wk 24 Colesevelam (3.8 g/d) significantly reduced LDL-C by 15% (P<0.001 vs placebo) and significantly increased HDL-C by 3% (P=0.04 vs placebo). TG concentrations vs baseline were significantly increased in both the placebo and colesevelam groups (by 5% and 10%, respectively), although the difference between the placebo and colesevelam groups was not statistically significant. Placebo (n=88) Colesevelam 3.8 g/d (n=95) * *P<0.001 vs placebo. †P=0.04 vs placebo. Insull et al. Mayo Clin Proc. 2001;76:971. Insull W Jr, Toth P, Mullican W, et al. Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary hypercholesterolemia: A 24-week, randomized controlled trial. Mayo Clin Proc. 2001;76:

Pharmacologic Therapy: Fibrates
Inhibit hepatic TG production and increase HDL production Used to treat elevated TG (20%-50% ) and low HDL-C (10%-20% ) Variable effect on LDL-C Side effects Dyspepsia, gallstones, myopathy Increased with statins Contraindicated in patients with severe renal or hepatic disease Fibrates inhibit production of TG by the liver and increase HDL-C production. Plasma level of TG is reduced by 20%-50%. Plasma level of HDL-C is increased by 10%-20%. Depending on the patient’s plasma TG concentration, fibrates have a variable effect on plasma LDL-C concentration. Side effects associated with fibrates include dyspepsia, gallstones, and myopathy; their incidence is increased in combination with statins. Fibrates are contraindicated in patients with severe renal or hepatic disease. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Executive Summary of 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). JAMA. 2001;285:

Limitations of Current Intestinal-Acting Agents
Bile acid sequestrants Noncompliance GI tolerability Reduced absorption of lipid-soluble vitamins May increase TG in patients with hypertriglyceridemia Plant stanol and sterol esters Lack of selectivity Some patients may find difficult to incorporate into diet May reduce absorption of lipid-soluble vitamins Despite their ability to reduce LDL-C, clinical use of both bile acid sequestrants and plant stanol and sterol esters is limited by several factors. Principal limitations of bile acid sequestrants include inadequate compliance, relatively poor GI tolerability, reduced absorption of lipid-soluble vitamins, and potential for increase in TG in patients with hypertriglyceridemia. Plant stanol and sterol esters are limited by the lack of selectivity for cholesterol, and some patients may find it difficult to incorporate them into their diet. In addition, these agents have been reported to reduce absorption of lipid-soluble vitamins.

Ezetimibe — Localizes at Brush Border of Small Intestine
Ezetimibe, a selective cholesterol absorption inhibitor, localizes and appears to act at the brush border of the small intestine and inhibits cholesterol absorption This results in A decrease in the delivery of intestinal cholesterol to the liver A reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood

Ezetimibe and Statins Complementary Mechanisms
Ezetimibe reduces the delivery of cholesterol to the liver Statins reduce cholesterol synthesis in the liver The distinct mechanism of ezetimibe is complementary to that of statins The effects of ezetimibe, either alone or in addition to a statin, on cardiovascular morbidity or mortality have not been established Knopp RH. N Engl J Med. 1999;341:498–511.

Coadministration: Simvastatin + Ezetimibe
EZE 10 mg (n = 11) Placebo (n = 11) SIMVA 10 mg (n = 12) -3.2 -10 -20 Mean Percent Change in LDL-C From Baseline -30 -34.9* -40 17% *P < 0.01 vs placebo †P < 0.01 vs simvastatin 10 mg -50 -51.9*† -60 Stein, E. Eur Heart J. 2001;3(suppl E):E14.

w-3 Fatty Acids Evidence: Effect on Lipid Parameters
27 patients with hypertriglyceridemia and low HDL-C treated with w-3 fatty acid (4 grams/day) for 7 months Total Cholesterol Triglyceride -10 -20 % Reduction -21* -30 -40 Omega 3 fatty acids are another strategy available to lower triglyceride levels. -46* -50 HDL-C=High-density lipoprotein cholesterol *P<0.05 Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18: 114 114

Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS)
w-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 w-3 fatty acids provide CV benefit, particularly in secondary prevention The JELIS trial randomized 18,645 hypercholesterolemic patients in Japan to receive either 1800 mg of EPA daily with a statin (EPA group; n=9326) vs. a statin alone (controls; n=9319). After a 5-year follow-up, the primary endpoint of any major coronary event was reduced from 3.5% in the statin alone group to 2.8% in the EPA + statin group (RRR 19% p=0.011). In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18%, but this finding was not significant (1.4% in the EPA group vs 1.7% in the control group; p=0.132). Years CV=Cardiovascular, EPA=Eicosapentaenoic acid *Composite of cardiac death, myocardial infarction, angina, PCI, or CABG Source: Yokoyama M et al. Lancet. 2007;369:1090-8 115 115

w-3 Fatty Acids Evidence: Secondary Prevention
Diet and Reinfarction Trial (DART) 2,033 men with a history of a MI randomized to a diet of reduced fat with an increased ratio of polyunsaturated to saturated fat, increased fatty fish intake*, or increased fiber intake for 2 years w-3 fatty acids reduce all cause mortality** after a MI w-3 Fatty Acids Placebo All cause mortality (%) In the Diet and Reinfarction Trial (DART), 2033 men with a history of MI received one of three dietary recommendations: (a) reduced fat and increased ratio of polyunsaturated to saturated fat, (b) increased fatty fish intake, or (c) increased fiber intake. The fish group was advised to eat at least 2 portions of fatty fish (300 grams total), corresponding to a weekly intake of about 2.5 grams of eicosapentaenoic acid (EPA). Those who could not tolerate this fish intake were advised to supplement it with fish oil capsules. Those advised to eat fatty fish had a 29% relative decrease in two year all-cause mortality compared with the other two groups. EPA=Eicosapentaenoic acid, MI=Myocardial infarction *Corresponds to 2.5 grams of EPA (PUFA) **p<0.05 Source: Burr ML et al. Lancet 1989;2: 116

w-3 fatty acids provide significant CV benefit after a MI
w-3 Fatty Acids Evidence: Secondary Prevention Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI-Prevenzione) 11,324 patients with a history of a MI randomized to w-3 polyunsaturated fatty acids [PUFA] (1 gram), vitamin E (300 mg), both or none for 3.5 years w-3 fatty acids provide significant CV benefit after a MI Percent of patients P=0.048 P=0.053 P=0.023 P=0.008 stroke 2 4 6 8 10 12 14 16 Death, NF MI, NF stroke (2 way) CV death, and NF (4 way) w-3 PUFA Placebo The GISSI trial randomized 11,324 patients with a history of MI to n-3 polyunsaturated fatty acids (PUFA) (1 gram daily), vitamin E (300 mg daily), both, or none for 3.5 years. Patients treated with n-3 PUFA, but not vitamin E, had a significantly lowered risk of the primary end point (a composite of death, nonfatal MI, and stroke). Treatment with n-3 PUFA decreased the relative risk of one primary end point by 10% in a two-way analysis (p=0.048) and 15% in a four-way analysis (p=0.023). Of note, the dose of n-3 PUFA used in this study (1 gram daily) is the dose recommended for patients with coronary heart disease, but is lower than the dose approved for triglyceride lowering (2-4 gram daily). CV=Cardiovascular, MI=Myocardial infarction, NF=Non-fatal, PUFA=Polyunsaturated fatty acids Source: GISSI Investigators. Lancet 1999;354: 117 117

Rate of reinfarction, stroke, or death* (%)
w-3 Fatty Acids Evidence: Secondary Prevention OMEGA Trial 3,827 patients 3-14 days following a MI randomized to w-3 fatty acids (460 mg EPA mg DHA) or placebo for 1 year w-3 fatty acids provide no benefit following a MI in those with high utilization of risk reducing therapies 12 10.4 8.8 8 Rate of reinfarction, stroke, or death* (%) 4 P=0.10 Placebo Fatty acids Omega-3 fatty acid supplementation does not seem to help in persons who are on aspirin, a statin, and antihypertensive therapy, at least in the short-term. DHA=Docosahexaenoic acid, EPA=Eicosapentaenoic acid, MI=Myocardial infarction *This is a secondary endpoint Source: Senges J et al. Presented at the Annual Scientific Sessions of the American College of Cardiology, March 2009, Orlando, FL 118

CONCLUSIONS Many persons with normal total or LDL-C levels still suffer CHD events. While statin-based clinical trials significantly reduce risk of CHD, residual risk still exists. Non-HDL-C, which reflects all the atherogenic lipid fractions, appears to be a stronger predictor of CHD events than LDL-C. The measurement of non-HDL-C and its use as a secondary therapeutic target is warranted to better address residual CHD risk. Lifestyle therapies as well as pharmacologic approaches, particular combination therapy with statins and other agents, are important for optimizing the entire lipid profile.

New Concepts in the Evaluation and Treatment of Dyslipidemia

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New Concepts in the Evaluation and Treatment of Dyslipidemia

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