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New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and Director Heart Disease Prevention Program Division.

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Presentation on theme: "New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and Director Heart Disease Prevention Program Division."— Presentation transcript:

1 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

2 Chylomicron Remnants VLDL LDL-R HDL 2 HDL3DL 3 Particle Size (nm) Density (g/ml) Chylomicron VLDL Remnants Lipoprotein Particles Lp(a) IDL Only these lipoprotein particles found in plaque at biopsy

3 The Apo B-containing (non-HDL) Lipoprotein Family: All Atherogenic *ApoB is a component of all lipoprotein particles currently considered atherogenic 2 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: Grundy SM. Circulation. 2002;106: Kunitake ST et al. J Lipid Res. 1992;33: Images available at: Accessed January Adapted with permission. ApoB* LDL ApoB-containing lipoproteins 1 – LDL—most common/most important – IDL – VLDL /VLDL remnants – Chylomicron remnants – Lp(a)

4 Rationale for therapeutic lowering of Apo B lipoproteins: decrease the probability of inflammatory response to retention Tabas I et al. Circulation. 2007;116: Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15: Hoshiga M et al. Circ Res. 1995;77: Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25: Merrilees MJ et al. J Vasc Res. 1993;30: Nakata A et al. Circulation. 1996;94: Steinberg D et al. N Engl J Med. 1989;320: High Plasma Apo B Lipoprotein Levels Promote Atherogenesis Blood Apo B lipoprotein particles Modification Macrophage Monocytes bind to adhesion molecules Smooth muscle Foam cell Inflammatory response

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

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

7

8 Total Cholesterol Distribution: CHD vs Non-CHD Population Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 1996 Reprinted with permission from Elsevier Science. 35% of CHD Occurs in People with TC<200 mg/dL Total Cholesterol (mg/dL) No CHD CHD Framingham Heart Study—26-Year Follow-up

9 Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal Risk of CHD by HDL-C and Total-C levels; aged 48–83 y Castelli WP et al. JAMA 1986;256:2835– < 4040–4950–59  60 < – –229  260 HDL-C (mg/dL) Total-C (mg/dL) 14-y incidence rates (%) for CHD

10 Sarwar N, et al. Circulation. 2007;115: a Individuals 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 Risk Ratio* (95% CI) 1.72 (1.56–1.90) 2 1 Duration of follow-up ≥10 years 5902 <10 years 4256 Sex Male 7728 Female 1994 Fasting status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 N=262,525 GroupsCHD Cases Overall CHD Risk Ratio a Decreased Risk Increased Risk CHD=coronary heart disease HDL=high-density lipoprotein Triglyceride Level Is Significant CHD Risk Factor: Recent Meta-Analysis of 29 Studies (n=262,525) (Sarwar et al., Circulation 2007)

11  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 *Reasons why non–HDL-C is stronger than LDL-C as predictor of cardiovascular disease How Can Hypertriglyceridemia be Atherogenic?

12 Apolipoprotein B LDL= 130 mg/dL Fewer Particles More Particles Cholesterol ester More apolipoprotein B Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i. Correlates with: TC198 mg/dL LDL-C 130 mg/dL TG 90 mg/dL HDL-C 50 mg/dL Non – HDL-C148 mg/dL Correlates with: TC 210 mg/dL LDL-C 130 mg/dL TG 250 mg/dL HDL-C 30 mg/dL Non – HDL-C180 mg/dL TC=total cholesterol, LDL-C=low-density lipoprotein cholesterol, TG=triglycerides, HDL-C=high-density lipoprotein cholesterol Elevated Triglycerides Are Associated With Increased Small, Dense LDL Particles

13  Cholesterol per particle, BUT  Subendothelial penetration  Subendothelial binding  Oxidized/modified  LDL-receptor clearance LDL=low-density lipoprotein Why Is Small, Dense LDL More Atherogenic?

14 Very–low-density lipoprotein (VLDL)  Made in the liver  Triglycerides (TG) >> cholesterol esters (CE)  Carries lipids from the liver to peripheral tissues HDL LDL IDL VLDL Atherogenic Lipoproteins Non-HDL; Apo B-100—containing Intermediate-density lipoprotein (IDL) Formed from VLDL due to lipase removal of TG Also known as a VLDL remnant Low-density lipoprotein (LDL) Formed from IDL due to lipase removal of TG CE >> TG High-density lipoprotein (HDL) Removes cholesterol from peripheral tissues Lp(a) Lipoprotein (a) Formed from LDL w/addition of apolipoprotein A Atherogenic and prothrombotic Non-HDL Includes All Atherogenic Lipoprotein Classes

15 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:

16 Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA. 1996;276: RR Lp(a) TC HDL-C HT GI Smoking

17 Placebo - Statin outcome trials High-risk CHD patients (high cholesterol) High-risk CHD patients (high cholesterol) Majority of CHD patients (broad range of cholesterol levels) Patients at high risk of CHD (high of CHD (high cholesterol) cholesterol) Patients at low Patients at low risk of CHD risk of CHD (low HDL-C) (low HDL-C) Primary prevention Secondary prevention WOSCOPS (pravastatin) AFCAPS/TexCAPS (lovastatin) 4S (simvastatin) HPS (simvastatin) CARE (pravastatin) LIPID (pravastatin) Continuum of risk Placebo MI rate per 100 subjects per 5 years PROSPER (pravastatin) Heart failure Heart failure CORONA GISSI-HF (rosuvastatin) End stage 53.7 JUPITER (rosuvastatin)

18 LDL-C achieved mg/dL (mmol/L) WOSCOPS – Placebo AFCAPS - Placebo ASCOT - Placebo AFCAPS - RxWOSCOPS - Rx ASCOT - Rx 4S - Rx HPS - Placebo LIPID - Rx 4S - Placebo CARE - Rx LIPID - Placebo CARE - Placebo HPS - Rx (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 LDL cholesterol and benefit in clinical trials Is lower better ? JUPITER TNT

19 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

20 HPS: First Major Coronary Event Nonfatal MI Coronary death Subtotal: MCE Coronary Noncoronary Subtotal: any RV Any MVE Coronary events Revascularizations Type of Major Vascular Event Statin- Allocated (n = 10269) Placebo- Allocated (n = 10267) 357 (3.5%) 574 (5.6%) 587 (5.7%) 707 (6.9%) 898 (8.7%)1212 (11.8%) 513 (5.0%)725 (7.1%) 450 (4.4%)532 (5.2%) 939 (9.1%) 1205 (11.7%) 2033 (19.8%)2585 (25.2%) 0.73 (0.67  0.79) P < (0.70  0.83) P < (0.72  0.81) P < Statin BetterPlacebo Better Heart Protection Study Collaborative Group. Lancet. 2002;360:7  22.

21 HPS—Simvastatin: Vascular Events by Baseline LDL-C Baseline LDL-C (mg/dL) Statin (n = 10,269) Placebo (n = 10,267) < (16.4%) 358 (21.0%) 100– (18.9%) 871 (24.7%)  (21.6%) 1356 (26.9%) All patients 2033 (19.8%) 2585 (25.2%) Event Rate Ratio (95% CI) Statin BetterStatin Worse (0.72–0.81) P <

22 Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study Follow-up (months) 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: HMG-CoA Reductase Inhibitor: Secondary Prevention 4,162 patients with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months

23 TNT: Rationale (1.6)(2.1)(2.6)(3.1)(3.6)(4.1)(4.7)(5.2) Atorvastatin 80 mg Atorvastatin 10 mg Screening TNT ? Adapted from LaRosa et al. N Engl J Med. 2005:352: LDL-C, mg/dL (mmol/L) Patients With CHD Events (%)

24 TNT: Changes in LDL-C by Treatment Group FinalScreen P <.001 Baseline Mean LDL-C (mmol/L) Mean LDL-C level = 101 mg/dL (2.6 mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L) LaRosa et al. N Engl J Med. 2005;352: Mean LDL-C (mg/dL) Study Visit (Months)

25 TNT: Primary Efficacy Outcome Measure: Major Cardiovascular Events* *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. LaRosa et al. N Engl J Med. 2005;352: HR=0.78 (95% CI 0.69, 0.89); P<.001 Proportion of Patients Experiencing Major Cardiovascular Event Atorvastatin 10 mg Atorvastatin 80 mg Relative risk reduction 22% Time (Years) Mean LDL-C level = 77 mg/dL Mean LDL-C level = 101 mg/dL

26 Recent Coronary IVUS Progression Trials Median change in percent atheroma volume (%) Mean LDL-C (mg/dL) REVERSAL pravastatin REVERSAL atorvastatin CAMELOT placebo A-Plus placebo ACTIVATE placebo Relationship between LDL-C and Progression Rate ASTEROID rosuvastatin Nissen SE, Nicholls S et al. JAMA 2006;295:1555–1565

27 Residual CVD Risk in Statin vs Placebo Trials 4 HPS Collaborative Group. Lancet. 2002;360: Shepherd J et al. N Engl J Med. 1995;333: Downs JR et al. JAMA. 1998;279: S Group. Lancet. 1994;344: LIPID Study Group. N Engl J Med. 1998;339: Sacks FM et al. N Engl J Med. 1996;335:  LDL N %-28%-29%-26%-25% SecondaryHigh RiskPrimary Patients Experiencing Major CHD Events, % 4S 1 LIPID 2 CARE 3 HPS 4 WOSCOPS 5 AFCAPS/TexCAPS 6 Placebo Statin Many CHD Events Still Occur in Statin-Treated Patients 25-40% CVD Reduction Leaves High Residual Risk

28 Antioxidative Activity Antithrombotic Activity Potential Antiatherogenic Actions of HDL Anti-infectious Activity Endothelial Repair Chapman MJ et al. Curr Med Res Opin. 2004;20: Assmann G et al. Annu Rev Med. 2003;53: Antiapoptotic Activity Reverse Cholesterol Transport Cellular Cholesterol Efflux Anti-inflammatory Activity Vasodilatory Activity HDL Apo A-I Apo A-II

29 Should High-Density Lipoprotein Be a Target of Therapy? Should High-Density Lipoprotein Be a Target of Therapy?

30 MARS MAAS PLAC I LCAS PLAC I CCAIT LCAS MAAS MARS ASTEROID CCAIT * ASTEROID rosuvastatinMAAS simvastatin CCAIT lovastatin MARS lovastatin LCAS fluvastatinPLAC I pravastatin Change in % stenosis per year On-treatment HDL-C (mg/dL) Change in Percent Diameter Stenosis vs On-treatment HDL-C in QCA Trials Placebo Statin * Ballantyne CM, Nicholls S et al. Circulation 2008; Online

31 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

32 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

33 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% Rössner S et al. Atherosclerosis. 1987;64: Wood PD et al. N Engl J Med. 1988;319: Ornish D et al. JAMA. 1998;280: Lifestyle Modifications to Raise HDL-C Levels 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:

34 Available Agents for HDL-C Raising AgentHDL-C ↑ Primary Use Nicotinic acid15-35% 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. *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:

35 Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) CHD Death or Nonfatal MI (%) Placebo 5.9 Fenofibrate P= % RRR 9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 years A fibrate does not provide significant additional benefit* in diabetics Source: Keech A et al. Lancet 2005;366: *Unadjusted for concomitant statin use CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Fibrate Evidence: Primary Prevention

36 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 CV death, nonfatal stroke or nonfatal MI (%/year) Placebo 2.4 Fenofibrate P=0.32 8% RRR Source: ACCORD study group. NEJM 2010;Epub ahead of print CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction

37 Is Niacin Useful in Low HDL-C?

38 HATS: Percent Change in Stenosis Change (%) *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: PlaceboAntioxidantSimvastatin/ Simvastatin / Vitamins*Niacin † Niacin/ Antioxidants ‡

39 Simvastatin-niacin 97% All placebos 76% RR = 0.10 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 (%) Years

40 Study Treatme nt n/N Control n/N Peto OR 95% Cl Peto OR 95% Cl ARBITER-6- HALTS 2/1879/ (0.08, 0.84) Guyton JR et al1/6761/ (0.02, 7.56) AFREGS0/711/ (0.00, 6.92) ARBITER-22/872/ (0.13, 6.65) HATS1/385/ (0.05, 1.26) UCSF_SCOR0/481/ (0.00, 6.96) STOCKHOLM72/279100/ (0.43, 0.88) CLAS1/945/ (0.05, 1.29) CDP287/ / (0.69, 0.94) Total Test for heterogeneity: P = 0.24, I 2 = 23.0% Test for overall effect: P < (0.65, 0.86) Subtotal excluding CDP 0.53 (0.38, 0.73) Log scale Meta-Analysis: Effects of Nicotinic Acid Pre-AIM-HIGH Trials: Major Coronary Events Many of these trials were tests of drug combinations that included niacin. Bruckert E et al. Atherosclerosis. 2010;210:

41 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 Investigators. N Engl J Med. 2001;365: AIM-HIGH Investigators. Am Heart J. 2011;161: e2.

42 Boden WE. N Engl J Med. epub 15 Nov 2011; doi /NEJMoa AIM-HIGH — Results HDL-C at Baseline and Follow-up

43 1 o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization Boden WE. N Engl J Med. epub 15 Nov 2011; doi /NEJMoa AIM-HIGH — Results Primary Outcome

44 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

45 Emerging HDL-C Therapies CETP Antagonism

46 Role of CETP in Atherosclerosis  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: Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28: LIVERPERIPHERAL TISSUE CE TG Bile Foam cells RCT HDL ABC-A1 VLDL LDL PLASMA LDL-R ABC-G1 Free cholesterol CETP Athero- sclerosis LDL

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

48 Lipid Effects of CETP Inhibitors/Modulators % Change from Baseline CETP Agent Dose (mg/day) HDL-C (%) LDL-C (%) TG (%) Torcetrapib Anacetrapib Evacetrapib Dalcetrapib Adapted from Cannon C et al. JAMA. 2011;306: Nicholls SJ et al. JAMA. 2011;306:

49 Torcetrapib “Beneficial” Effects on Lipoproteins Is the toxicity of torcetrapib related to the mechanism or the molecule? Placebo60 mg90 mg120 mg Barter PJ et al. N Engl J Med. 2007;357: HDL-C LDL-C +42% +49% +55% -20% -18% -1% +1%

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

51 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 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 inhibition 1,2 1. Barter PJ et al. N Engl J Med. 2007;357: Rosenson RS. Curr Athero Rep. 2008;10:

52 dal-OUTCOMES Results: Isolated ↑HDL-C LDL Cholesterol (mg/dL) HDL Cholesterol (mg/dL) Schwartz GG et al. N Engl J Med Nov 5. [Epub ahead of print]. No. at risk Placebo Dalcetrapib No. at risk Placebo Dalcetrapib Months

53 dal-OUTCOMES Results: No ↓CVD Schwartz GG et al. N Engl J Med Nov 5. [Epub ahead of print]. Year Cumulative Incidence of Primary Outcome (% of patients) No. at risk Placebo Dalcetrapib

54 Anacetrapib Effects on LDL-C and HDL-C HDL-C Baseline HDL-C (mg/dL) (SE) Anacetrapib Placebo Anacetrapib n = Placebo n = LDL-C Study Week Baseline LDL-C (mg/dL) (SE) Anacetrapib Placebo Anacetrapib n = Placebo n = % ( P <0.001) % ( P <0.001) Cannon CP et al. N Engl J Med. 2010;363: Study Week

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

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

57 Change in Calculated LDL-C at 2 Weekly Intervals from Baseline to Week 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 Mean (  SE) % Change from Baseline ∆ - 8.5% ∆ % ∆ % ∆ % ∆ % ∆ - 5.1% ∆ % ∆ %

58 LDL-C from Baseline to Week 12 by Treatment Group (mITT Population)

59 HoFH Disease Overview  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 1.Goldberg AC, et al. Journal of Clinical Lipidology. (2011); 5(3 Suppl):S1-S8. 2.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 Rader DJ, et al. J Clin Invest. 2003;111: Raal FJ, Santos RD. Atherosclerosis. (2012); 223(2): ©2013 Aegerion Pharmaceuticals, Inc. Adapted from PRC approved NLA symposium slide and SAG mock

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

61 Clinical Characteristics FH Tendinous Xanthomas (any age) Corneal Arcus (<45yo) Xanthelasma (<25yo)

62 Consequences of Markedly Elevated LDL-C in HoFH patients : ● Typically develop cardiovascular disease before the age of 20 1 ● 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 years 2 ● 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): HoFH Impact on the Patient ©2013 Aegerion Pharmaceuticals, Inc.

63 LDL Apheresis is Current Recommended Care for HoFH Schematic courtesy of D. Rader EMDAC Slides FINAL CM-015 ©2013 Aegerion Pharmaceuticals, Inc.

64 LDL-C Levels Decrease and then Rebound Following Apheresis Adapted from Thompsen J & Thompson PD. Atherosclerosis. 2006;189: EMDAC Slides FINAL CM-017 Pre-treatment LDL level 2-week interval LDL CHOLESTEROL Start of LDL apheresis Baseline LDL TIME Post-treatment LDL level ©2013 Aegerion Pharmaceuticals, Inc.

65 New Lipid-Lowering Therapies Approved in the US for Use in HoFH Drug and dosageIndication in HoFH Lomitapide 1 Approved Dec 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 Mipomersen 2 Approved Jan 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. ©2013 Aegerion Pharmaceuticals, Inc. 1.Juxtapid™ (lomitapide) capsules [US prescribing information]. Cambridge, MA: Aegerion Pharmaceuticals; Kynamro™ (mipomersen sodium) Injection [US prescribing information]. Cambridge, MA: Genzyme Coorporation; New Slide

66 Microsomal Triglyceride Transfer Protein (MTP) 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 membranes 1 Normal concentrations and function of MTP are necessary for the proper assembly and secretion of apo B-containing lipoproteins in the liver and intestines 2 1. Hussain M, et al. Journal of Lipid Research. 2003:44; Liao W, et al. Journal of Lipid Research. 2003:44; Liver Cell ER Lumen Cytoplasm MTP Intestinal Epithelial Cell ER Lumen Cytoplasm MTP PRC- Approved Sales Training Module 4; PRC Approved NLA- spring symp slide ©2013 Aegerion Pharmaceuticals, Inc.

67 MTP Inhibitors – Mechanism of Action MTP inhibitors 1,2  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; Hussain MM, et al. Nutrition Metabolism. 2012:9;14. PRC- Approved Sales Training Module 4; PRC Approved NLA- spring symp slide ©2013 Aegerion Pharmaceuticals, Inc.

68 Phase 2 Study Design 6 Patients 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 OR -TC >500 mg/dl + TGs 250mg/dl 4 weeks Cuchel, M. et al. NEJM 2007; 356: 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 0.3 mg/kg Lomitapide 0.1 mg/kg Lomitapide 1.0 mg/kg Washout 4 weeks Adapted from EMDAC CM -028 and original MI slide deck Changed AGER-733 to lomitapide ©2013 Aegerion Pharmaceuticals, Inc.

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

70 Antisense Oligonucleotides and Apo B Synthesis Inhibition Brautbar A and Ballantyne CM. Nat Rev Cardio 2011;8:253.

71 Mipomersen and LDL Lowering in Homozygous FH Baseline LDL-C: 405 mg/dl n=17 n=34 Raal F. Lancet 2010;375: mg SC/Q week

72 What’s New in the Cholesterol Guideline? 1)Focus on ASCVD reduction: 4 Statin Benefit Groups 2)New Perspective on LDL-C and/or Non-HDL-C Treatment Goals 3)Global Risk Assessment for Primary Prevention 4)Safety Recommendations 5)Role of Biomarkers and Noninvasive Tests 6)Future Updates to Guidelines

73 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

74 Why Not Continue to Treat to Target? Major difficulties: 1.Current RCT data do not indicate what the target should be 2.Unknown magnitude of additional ASCVD risk reduction with one target compared to another 3.Unknown rate of additional adverse effects from multidrug therapy used to achieve a specific goal 4.Therefore, unknown net benefit from treat-to- target approach

75 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.

76 4 Statin Benefit Groups (Revised Figure) IA IB IA IIaB 1

77 Clinical Flow (Revised Figure-con’t)

78 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.

79 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

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

81 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! Primary Prevention Statin Therapy

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84 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

85 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 IIaIIbIII

86 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. Optimizing Statin Therapy

87 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. I IIaIIbIII Insufficient Response to Statin Therapy

88 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) Insufficient Response to Statin Therapy (cont.) †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.

89 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.

90 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) Insufficient Response to Statin Therapy (cont.)

91 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. Insufficient Response to Statin Therapy (cont.) ‡ 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.

92 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 IIaIIbIII Insufficient Response to Statin Therapy (cont.)

93 Safety RCTs & meta-analyses of RCTs used to identify important safety considerations Allow estimation of net benefit from statin therapy o 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

94 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

95 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

96 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

97 Non-Statin Therapies 1)Ezetimibe – Additional 15% lowering of LDL-C – No known benefit for reducing CVD events beyond statin therapy – awaiting IMPROVE-IT clinical trial 2)Bile Acid Resins 3)Niacin 4)Fibrates (Fenofibrate) 5)Therapies for HoFH (Lomitapide, Mipomersin) Emerging Therapies in Development 1)CETP Inhibitors (Anacetrapib and Evacetrapib) 2)PCSK9 Inhibitors

98 Three Principles  Do not focus on LDL–C or non-HDL-C cholesterol levels as treatment goals o 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)

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

101 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 saturated and trans fat restriction dietary salt restriction dietary salt restriction  Evidence to support dietary cholesterol restriction in those who could benefit from  LDL-C is inadequate.

102 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). 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. 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. LDL-C: Advise adults who would benefit from LDL-C lowering* to: I IIaIIbIII *Refer to 2013 Blood Cholesterol Guideline for guidance on who would benefit from LDL-C lowering.

103 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. LDL-C: Advise adults who would benefit from LDL-C lowering* to: (cont.) I IIaIIbIII I IIaIIbIII *Refer to 2013 Blood Cholesterol Guideline for guidance on who would benefit from LDL-C lowering. I IIaIIbIII

104 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. Physical Activity I IIaIIbIII I IIaIIbIII

105 ……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)….

106 Lipid Management Recommendations 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. For all patients

107 Therapeutic Lifestyle Changes Nutrient Composition of TLC Diet NutrientRecommended Intake  Saturated fat Less than 7% of total calories  Polyunsaturated fatUp to 10% of total calories  Monounsaturated fat Up to 20% of total calories  Total fat25–35% of total calories  Carbohydrate50–60% of total calories  Fiber20–30 grams per day  Protein Approximately 15% of total calories  CholesterolLess than 200 mg/day  Total calories (energy)Balance energy intake and expenditure to maintain desirable body weight

108 Possible Benefits From Other Therapies 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:

109 Dietary Adjuncts  TLC for patients with LDL-C = 160 Walden CE et al. Arterioscler Thromb Vasc Biol 1997;17: Jenkins DJ et al. Curr Opin Lipidol 2000;11: Cato N. Stanol meta-analysis. Personal communication, Dietary Component LDL-C  (mg/dL) Low saturated fat/dietary cholesterol –12 Viscous fiber (10–25 g/d) –8 –8 Plant stanols/sterols (2 g/d) –16 Total –36 mg/dl –36 mg/dl

110 % Reduction Triglyceride *P< * -21* Total Cholesterol Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18: patients with hypertriglyceridemia and low HDL-C treated with  -3 fatty acid (4 grams/day) for 7 months  -3 Fatty Acids Evidence: Effect on Lipid Parameters HDL-C=High-density lipoprotein cholesterol

111 Source: Yokoyama M et al. Lancet. 2007;369: Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS) *Composite of cardiac death, myocardial infarction, angina, PCI, or CABG Years  -3 Fatty Acids Evidence: Primary and Secondary Prevention 18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a statin or a statin alone for 5 years  -3 fatty acids provide CV benefit, particularly in secondary prevention CV=Cardiovascular, EPA=Eicosapentaenoic acid

112 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.


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