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)

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: 10

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 11

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 12

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 13

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 14

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) 17

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 18

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:

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 26

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: 27

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 30

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:

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: 35

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].

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:

The Role of PCSK9 in the Regulation of LDL Receptor Expression
For illustration purposes only

Impact of an PCSK9 mAb on LDL Receptor Expression
For illustration purposes only

Change in Calculated LDL-C at 2 Weekly Intervals from Baseline to Week 12
∆ % ∆ % ∆ % ∆ % ∆ % ∆ % ∆ % ∆ % LDL-C Mean (SE) % Change from Baseline Mean percentage change in calculated LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12 in the modified intent-to-treat (mITT) population, by treatment group. Week 12 estimation using LOCF method.

LDL-C from Baseline to Week 12 by Treatment Group (mITT Population)
Intervention Baseline LDL-C (mg/dL) Attained LDL-C (mg/dL) Placebo 130.2 120.5 SAR mg Q2W 123.2 73.2 SAR mg Q2W 127.0 46.0 SAR mg Q2W 123.9 34.2 SAR mg Q4W 128.2 71.1 SAR mg Q4W 131.6 66.0

Adapted from PRC approved NLA symposium slide and SAG mock
HoFH Disease Overview Adapted from PRC approved NLA symposium slide and SAG mock HoFH is a serious life-threatening genetic disease characterized by extremely elevated blood LDL-C levels, premature atherosclerosis and increased risk of CV morbidity and mortality.1 HoFH usually presents in childhood, but patients may go undiagnosed until adulthood.2,3,4 Based on the genetic defect leading to LDL receptor dysfunction, patients have minimal response to existing pharmacologic therapies.5 Diagnostic criteria for HoFH in the literature are variable and not universally defined. However, the clinical diagnosis typically consists of the following:6 Significantly elevated levels of LDL-C Cutaneous and tendon xanthomas and corneal arcus Parental history of significant hypercholesterolemia and/or premature CVD DNA confirmation can be used when diagnosis is unconfirmed Goldberg AC, et al. Journal of Clinical Lipidology. (2011); 5(3 Suppl):S1-S8. Raal FJ, et al. Circulation. (2011); 124(20): Hoeg JM, et al. Atheroscler Thromb Vasc Biol. (1994);14(7): Taszner M, et al. 80th Eur Atherosclerosis Society Meeting. Milan, Italy. Abstract 1349 Rader DJ, et al. J Clin Invest. 2003;111: Raal FJ, Santos RD. Atherosclerosis. (2012); 223(2): ©2013 Aegerion Pharmaceuticals, Inc.

Patient with HoFH EMDAC Slide FINAL CM-006. 28 year-old female
Cutaneous xanthomas beginning at age 3 Obstructive coronary artery disease and CABG at age 12 LDL cholesterol = 780 mg/dL ©2013 Aegerion Pharmaceuticals, Inc.

Clinical Characteristics FH
Corneal Arcus (<45yo) Probability of xanthoma- age -10%; <50% have them All these findings have poor sensitivity for the diagnosis Xanthelasma (<25yo) Tendinous Xanthomas (any age)

HoFH Impact on the Patient
Consequences of Markedly Elevated LDL-C in HoFH patients: Typically develop cardiovascular disease before the age of 201 Coronary artery disease Myocardial infarction Severe aortic stenosis Heart failure Stroke Sudden death Even with currently existing therapies, the mean age of death is 33 years2 Joint symptoms such as tendonitis or arthralgias; unusual skin lesions - xanthomas Significant Unmet Medical Need 1. Goldstein, J. L. et al. (2001). The Metabolic and Molecular Basis of Inherited Disease. 2. Raal FJ, et al. Circulation. (2011); 124(20): ©2013 Aegerion Pharmaceuticals, Inc.

LDL Apheresis is Current Recommended Care for HoFH
EMDAC Slides FINAL CM-015 Plasma Line Dextran sulfate columns Plasma Pump Blood Withdrawal Blood Pump Heparin Pump Blood Return Plasma Separator Regeneration Pump Re-Priming Solution Waste Line Schematic courtesy of D. Rader ©2013 Aegerion Pharmaceuticals, Inc.

LDL-C Levels Decrease and then Rebound Following Apheresis
EMDAC Slides FINAL CM-017 Start of LDL apheresis Baseline LDL Pre-treatment LDL level LDL CHOLESTEROL Post-treatment LDL level 2-week interval TIME Adapted from Thompsen J & Thompson PD. Atherosclerosis ;189: ©2013 Aegerion Pharmaceuticals, Inc.

New Lipid-Lowering Therapies Approved in the US for Use in HoFH
New Slide Drug and dosage Indication in HoFH Lomitapide 1 Approved Dec 2012 5 mg orally, once daily- starting dose Dose can be escalated gradually based on acceptable safety and tolerability 60 mg orally, once daily- maximum recommended dose As an adjunct to a low-fat diet and other lipid lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL- C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Limitations of Use Safety and effectiveness have not been established in patients with hypercholesterolemia who do not have HoFH; Effect on cardiovascular morbidity and mortality has not been determined Mipomersen2 Approved Jan 2013 200 mg subcutaneous injection once weekly As an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). Limitations of Use: Safety and effectiveness have not been established in patients with hypercholesterolemia who do not have HoFH. Effect on cardiovascular morbidity and mortality has not been determined. Use as an adjunct to LDL apheresis is not recommended. Juxtapid™ (lomitapide) capsules [US prescribing information]. Cambridge, MA: Aegerion Pharmaceuticals; 2012. Kynamro™ (mipomersen sodium) Injection [US prescribing information]. Cambridge, MA: Genzyme Coorporation; 2013. ©2013 Aegerion Pharmaceuticals, Inc.

Microsomal Triglyceride Transfer Protein (MTP)
PRC- Approved Sales Training Module 4; PRC Approved NLA- spring symp slide MTP is an intracellular lipid-transfer protein found in the lumen of the endoplasmic reticulum (ER) responsible for binding and shuttling individual lipid molecules between membranes1 Normal concentrations and function of MTP are necessary for the proper assembly and secretion of apo B-containing lipoproteins in the liver and intestines2 Liver Cell ER Lumen Cytoplasm MTP Intestinal Epithelial Cell 1. Hussain M, et al. Journal of Lipid Research. 2003:44;22-32. 2. Liao W, et al. Journal of Lipid Research. 2003:44; ©2013 Aegerion Pharmaceuticals, Inc.

MTP Inhibitors – Mechanism of Action
PRC- Approved Sales Training Module 4; PRC Approved NLA- spring symp slide MTP inhibitors1,2 Prevent the assembly of apo B-containing lipoproteins in hepatocytes and enterocytes. This inhibits the synthesis of VLDL and chylomicrons. The inhibition of the synthesis of VLDL and intestinal chylomicron secretion lowers plasma lipids. 1. Wetterau JR, et al. Science. 1998:282; 2. Hussain MM, et al. Nutrition Metabolism. 2012:9;14. ©2013 Aegerion Pharmaceuticals, Inc.

Phase 2 Study Design Adapted from EMDAC CM -028 and original MI slide deck Changed AGER-733 to lomitapide Single arm, open label study 16-week treatment duration - lomitapide as monotherapy (no background lipid-lowering therapies) Dose escalated from a low starting dose (mean doses at each of the four titration steps were: 2.0, 6.7, 20.1, and 67.0 mg/day) Low-fat diet (prescribed diet of <10% energy from fat) Lomitapide 0.03 mg/kg Lomitapide 0.1 mg/kg Lomitapide 0.3 mg/kg Lomitapide 1.0 mg/kg 6 Patients Washout 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks Key Inclusion Criteria: Patients aged yrs. Clinical Diagnosis of HoFH and one of the following documented functional mutation in both LDL receptor alleles OR skin fibroblast LDL receptor activity <20% normal TC >500 mg/dl + TGs <300 mg/dl + both parents with TC >250mg/dl Cuchel, M. et al. NEJM 2007; 356: ©2013 Aegerion Pharmaceuticals, Inc.

Phase 2 HoFH Study: Efficacy 51% Reduction in LDL-C
EMDAc CM-029 51% Reduction p<0.001 Mean Dose (mg): 2.0 6.7 20.1 67.0 Cuchel, M. et al. NEJM 2007; 356: ©2013 Aegerion Pharmaceuticals, Inc.

Antisense Oligonucleotides and Apo B Synthesis Inhibition
How antisense oligonucleotides block translation and thus inhibit protein production. Protein synthesis is dependent upon a sequence of events that starts with the separation of the DNA strands and synthesis of messenger RNA (mRNA) from the ‘antisense’ strand. This mRNA contains all the information required for protein synthesis from the ‘sense’ DNA strand and migrates from the nucleus to the cytoplasm, where it serves as a template for protein synthesis. Antisense oligonucleotides bind the mRNA and block its translation. Brautbar A and Ballantyne CM. Nat Rev Cardio 2011;8:253.

Mipomersen and LDL Lowering in Homozygous FH
Baseline LDL-C: 405 mg/dl 200mg SC/Q week Raal F. Lancet 2010;375:

What’s New in the Cholesterol Guideline?
Focus on ASCVD reduction: 4 Statin Benefit Groups New Perspective on LDL-C and/or Non-HDL-C Treatment Goals Global Risk Assessment for Primary Prevention Safety Recommendations Role of Biomarkers and Noninvasive Tests Future Updates to Guidelines

on LDL–C & Non-HDL–C Goals
New Perspective on LDL–C & Non-HDL–C Goals Lack of RCT evidence to support titration of drug therapy to specific LDL–C and/or non-HDL–C goals Strong evidence that appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit Quantitative comparison of statin benefits with statin risk Nonstatin therapies – did not provide ASCVD risk reduction benefits or safety profiles comparable to statin therapy

Why Not Continue to Treat to Target?
Major difficulties: Current RCT data do not indicate what the target should be Unknown magnitude of additional ASCVD risk reduction with one target compared to another Unknown rate of additional adverse effects from multidrug therapy used to achieve a specific goal Therefore, unknown net benefit from treat-to-target approach

4 Statin Benefit Groups Clinical ASCVD*
LDL–C >190 mg/dL, Age >21 years Primary prevention – Diabetes: Age years, LDL–C mg/dL Primary prevention - No Diabetes†: ≥7.5%‡ 10-year ASCVD risk, Age years, LDL–C mg/dL, *Atherosclerotic cardiovascular disease †Requires risk discussion between clinician and patient before statin initiation. ‡Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator.

4 Statin Benefit Groups (Revised Figure)
IA IA IB IA IIaB 1

Clinical Flow (Revised Figure-con’t)
*The Pooled Cohort Equations can be used to estimate 10-year ASCVD risk in individuals with and without diabetes. A downloadable spreadsheet enabling estimation of 10-year and lifetime risk for ASCVD and a web-based calculator are available at and The calculator should be used to inform decision making in primary prevention patients not on a statin. †Consider moderate-intensity statin as more appropriate in low-risk individuals. ‡For those in whom a risk assessment is uncertain, factors such as primary LDL–C >160 mg/dL or other evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years of age in a first degree male relative or <65 years of age in a first degree female relative, lifetime risk of ASCVD, CAC score ≥300 Agatston units, or ≥75 percentile for age, sex, and ethnicity (For additional information, see ABI <0.9, or hs-CRP >2 mg/L. Additional factors that may aid in individual risk assessment may be identified in the future. §1) Potential ASCVD risk reduction benefits (e.g., absolute risk reduction from moderate- or high-intensity statin therapy can be approximated by using the estimated 10-year ASCVD risk and the relative risk reduction of ~30% for moderate-intensity statin or ~45% for high-intensity statin therapy. 2) Potential adverse effects. The excess risk of diabetes is the main consideration in ~0.1 excess case per 100 individuals treated with a moderate-intensity statin for 1 year and ~0.3 excess cases per 100 individuals treated with a high-intensity statin treated patients for 1 year. Note: a case of diabetes is not considered equivalent to a fatal or nonfatal MI or stroke. Both statin-treated and placebo-treated participants experienced the same rate of muscle symptoms. The actual rate of statin-related muscle symptoms in the clinical population is unclear. Muscle symptoms attributed to statin should be evaluated in as Table 8, Safety Rec 8.

Intensity of Statin Therapy
*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response. †Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al). ‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.

Global Risk Assessment
Primary Prevention Global Risk Assessment To estimate 10-year ASCVD* risk New Pooled Cohort Risk Equations White and black men and women More accurately identifies higher risk individuals for statin therapy Focuses statin therapy on those most likely to benefit You may wish to avoid initiating statin therapy in high-risk groups found not to benefit (higher grades of heart failure and hemodialysis) *10-year ASVD: Risk of first nonfatal myocardial infarction, coronary heart disease death, nonfatal or fatal stroke

Risk Reduction as Related to 5-year Risk Categories
Cholesterol Treatment Trialists’ Collaboration, The Lancet 2012

Primary Prevention Statin Therapy
Thresholds for initiating statin therapy derived from 3 exclusively primary prevention RCTs Before initiating statin therapy, clinicians and patients engage in a discussion of the potential for ASCVD risk reduction benefits, potential for adverse effects, drug-drug interactions, and patient preferences Calculators don’t write Rx, physicians do!

Individuals Not in a Statin Benefit Group
In those for whom a risk decision is uncertain: These factors may inform clinical decision making: Family history of premature ASCVD Elevated lifetime risk of ASCVD LDL–C ≥160 mg/dL hs-CRP ≥2.0 mg/L Coronary artery calcium (CAC) score ≥300 Agaston units Ankle brachial index (ABI)<0.9 Their use still requires discussion between clinician and patient

Monitoring Statin Therapy
Adherence to medication and lifestyle, therapeutic response to statin therapy, and safety should be regularly assessed. This should also include a fasting lipid panel performed within 4 to 12 weeks after initiation or dose adjustment, and every 3 to 12 months thereafter. Other safety measurements should be measured as clinically indicated. I IIa IIb III A

Optimizing Statin Therapy
The maximum tolerated intensity of statin should be used in individuals for whom a high- or moderate-intensity statin is recommended, but not tolerated.* * Several RCTs found that low and low-moderate intensity statin therapy reduced ASCVD events. In addition, the CTT meta-analyses of statin trials have shown that each 39 mg/dL reduction in LDL-C reduced CVD events by 22%. Therefore, the Panel considered that submaximal statin therapy should be used to reduce ASCVD risk in those unable to tolerate moderate- or high-intensity statin therapy.

Insufficient Response to Statin Therapy
IIa IIb III A In individuals who have a less-than-anticipated therapeutic response or are intolerant of the recommended intensity of statin therapy, the following should be performed: Reinforce medication adherence. Reinforce adherence to intensive lifestyle changes. Exclude secondary causes of hyperlipidemia.

Insufficient Response to Statin Therapy (cont.)
It is reasonable to use the following as indicators of anticipated therapeutic response to the recommended intensity of statin therapy. Focus is on the intensity of the statin therapy. As an aid to monitoring: High-intensity statin therapy† generally results in an average LDL-C reduction of ≥50% from the untreated baseline; (recommendation cont. below) †In those already on a statin, in whom baseline LDL-C is unknown, an LDL-C <100 mg/dL was observed in most individuals receiving high intensity statin therapy.

Insufficient Response to Statin Therapy(cont.)
(recommendation cont.) Moderate-intensity statin therapy generally results in an average LDL-C reduction of 30 to <50% from the untreated baseline; LDL-C levels and percent reduction are to be used only to assess response to therapy and adherence. They are not to be used as performance standards.

In individuals at higher ASCVD risk receiving the maximum tolerated intensity of statin therapy who continue to have a less-than-anticipated therapeutic response, addition of a nonstatin cholesterol-lowering drug(s) may be considered if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. (recommendation cont. below)

Higher-risk individuals include: Individuals with clinical ASCVD‡ <75 years of age Individuals with baseline LDL-C ≥190 mg/dL Individuals 40 to 75 years of age with diabetes Preference should be given to nonstatin cholesterol-lowering drugs shown to reduce ASCVD events in RCTs. ‡ Clinical ASCVD includes acute coronary syndromes, or a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of the atherosclerotic origin.

In individuals who are candidates for statin treatment but are completely statin intolerant, it is reasonable to use nonstatin cholesterol-lowering drugs that have been shown to reduce ASCVD events in RCTs if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. I IIa IIb III B

Safety RCTs & meta-analyses of RCTs used to identify important safety considerations Allow estimation of net benefit from statin therapy ASCVD risk reduction versus adverse effects Expert guidance on management of statin-associated adverse effects, including muscle symptoms Advise use of additional information including pharmacists, manufacturers prescribing information, & drug information centers for complex cases

Management of Muscle Symptoms on Statin Therapy
It is reasonable to evaluate and treat muscle symptoms including pain, cramping, weakness, or fatigue in statin-treated patients according to the management algorithm To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiating statin therapy

Management of Muscle Symptoms on Statin Therapy (con’t)
If unexplained severe muscle symptoms or fatigue develop during statin therapy: Promptly discontinue the statin Address possibility of rhabdomyolysis with: CK Creatinine urine analysis for myoglobinuria Re: word ‘severe’. I suggest coloring the text or underlining it so that it will stand out more prominently. I believe that italics will not draw everyone’s attention to this

Statin-Treated Individuals Nonstatin Therapy Considerations
Use the maximum tolerated intensity of statin Consider addition of a nonstatin cholesterol-lowering drug(s) If a less-than-anticipated therapeutic response persists Only if ASCVD risk-reduction benefits outweigh the potential for adverse effects in higher-risk persons: Clinical ASCVD <75 years of age Baseline LDL–C ≥190 mg/dL Diabetes mellitus 40 to 75 years of age Nonstatin cholesterol-lowering drugs shown to reduce ASCVD events in RCTs are preferred

Non-Statin Therapies Ezetimibe – Additional 15% lowering of LDL-C – No known benefit for reducing CVD events beyond statin therapy – awaiting IMPROVE-IT clinical trial Bile Acid Resins Niacin Fibrates (Fenofibrate) Therapies for HoFH (Lomitapide, Mipomersin) Emerging Therapies in Development CETP Inhibitors (Anacetrapib and Evacetrapib) PCSK9 Inhibitors

Three Principles Do not focus on LDL–C or non-HDL-C cholesterol levels as treatment goals Lipid panel to monitor adherence For those shown to benefit, use statins – inexpensive (5 of 7 generic) medications proven to reduce ASCVD risk In primary prevention decisions, use a clinician-patient discussion to determine: global risk reduction strategy potential for benefit and harms of statin therapy Patient preferences (shared decision making)

Lifestyle management remains the cornerstone for reducing cardiovascular disease risk including achieving and maintaining optimal lipid levels

What’s New in Lifestyle?
Recommendations based on in-depth systematic reviews. Previous reports used different methods and structure. More depth, less breadth. More emphasis on dietary patterns More data provided to support saturated and trans fat restriction dietary salt restriction Evidence to support dietary cholesterol restriction in those who could benefit from  LDL-C is inadequate.

LDL-C: Advise adults who would benefit from LDL-C lowering* to:
Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils and nuts; and limits intake of sweets, sugar-sweetened beverages, and red meats. Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes). Achieve this pattern by following plans such as the DASH dietary pattern, the U.S. Department of Agriculture (USDA) Food Pattern, or the AHA Diet. I IIa IIb III A *Refer to 2013 Blood Cholesterol Guideline for guidance on who would benefit from LDL-C lowering.

LDL-C: Advise adults who would benefit from LDL-C lowering. to: (cont
Aim for a dietary pattern that achieves 5% to 6% of calories from saturated fat. Reduce percent of calories from saturated fat. Reduce percent of calories from trans fat. I IIa IIb III A I IIa IIb III A I IIa IIb III A *Refer to 2013 Blood Cholesterol Guideline for guidance on who would benefit from LDL-C lowering.

Physical Activity A A Lipids:
IIa IIb III A Lipids: In general, advise adults to engage in aerobic physical activity to reduce LDL-C and non–HDL-C: 3 to 4 sessions a week, lasting on average 40 minutes per session, and involving moderate- to vigorous-intensity physical activity. BP: In general, advise adults to engage in aerobic physical activity to lower BP: 3 to 4 sessions a week, lasting on average 40 minutes per session, and involving moderate- to vigorous-intensity physical activity. I IIa IIb III A

Hospital Specialty_FINAL ATS
4/14/2017 9:33 PM ……even modest weight loss (3-5% of body weight) can result in clinically meaningful benefits for triglycerides, blood glucose, glycated hemoglobin, and development of diabetes (type 2)…. 105

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.

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: 110 110

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;369:1090-8 111 111

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

Similar presentations

Presentation on theme: "New Concepts in the Evaluation and Treatment of Dyslipidemia"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

New Concepts in the Evaluation and Treatment of Dyslipidemia

Similar presentations

Presentation on theme: "New Concepts in the Evaluation and Treatment of Dyslipidemia"— Presentation transcript:

Similar presentations

About project

Feedback