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:
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
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
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)
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
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
lipid core adventitia lipid core Anti-atherosclerotic therapy From Davies et al (1998) Unstable lesion Stable lesion
Proportion of U.S. Adults at Recommended Lipid Levels in NHANES Ghandehari and Wong et al, Am Heart J 2008
Genetic Causes of Dyslipidemia Type I – Familial Hyperchylomicronemia Fasting triglycerides > 1000 mg/dl Defect in lipoprotein lipase or apo CII Not necessarily at increased risk of CAD Type II - Familial Hypercholesterolemia (type II) LDL-C > 95 th percentile for age and gender CAD in men by 3 rd or 4 th decade Defect in LDL receptor Autosomal dominant inheritance Prevalence 1:500 Familial Defective apo B 100 Defective apo B alters LDLr handling Previously undetecable from FH
Genetic Causes of Dyslipidemia Type III – Hyperlipoproteinemia Increased TC, VLDL, decreased HDL; Increased VLDL:TG Defect in apo E results in increased concentration of remnant particles Rare Type IV – Familial Hypertriglyceridemia Increased TC (due to VLDL), TG, decreased LDL, HDL Results from hepatic overproduction of VLDL Prevalence 1:100 – 1:50; Association with CAD not as strong as FH Heterogeneous inheritance Very sensitive to diet and EtOH Type V Increase in chylomicrons and VLDL Rare
Genetic Causes of Dyslipidemia Familial Combined Hyperlipidemia Increased TC, LDL and/or triglycerides; decreased HDL Most common genetic dyslipidemia: prevalence 1:50 Heterogenous inheritance Accounts for 10-20% of patients with premature CAD Defects in HDL Metabolism Most often low HDL is secondary to other dyslipidemia Not all associated with increased CAD risk (e.g. apo AI Milano ) Tangier’s Disease CETP defects result in increased HDL
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
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
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)
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?
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
Cholesterol per particle, BUT Subendothelial penetration Subendothelial binding Oxidized/modified LDL-receptor clearance LDL=low-density lipoprotein Why Is Small, Dense LDL More Atherogenic?
Significance of Non-HDL-C LDL-C levels incompletely measure the total atherogenic burden When serum TG are >200 mg/dL, increased remnant atherogenic lipoproteins heighten risk beyond predicted by LDL-C –Associated with substantially elevated VLDL-C VLDL-C and IDL-C are not accounted for by the calculation of LDL-C Non-HDL-C = cholesterol concentration of all atherogenic lipoproteins Miller M, et al. Am J Cardiol 2009;101: Non-HDL-Cholesterol and CVD Risk
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
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 RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA. 1996;276: RR Lp(a) TC HDL-C HT GI Smoking
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)
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 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.
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
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 (%)
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)
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
Meta analysis of moderate vs aggressive statin therapy Cannon et al (2006) JACC 48:438 Coronary death or MI ACS Stable CHD
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
Rosuvastatin 40 mg (n=349 for IVUS analysis; n=292 for QCA analysis) Patients (≥18 years) CAD, undergoing coronary angiography Target coronary artery: ≤50% reduction in lumen diameter of ≥40 mm segment Target segment for QCA: all segments >25% at baseline No cholesterol entry criteria Visit: Week: Lipids Lipids Tolerability IVUS QCA Lipids Tolerability Lipids Tolerability Tolerability 1 – Eligibility assessment ASTEROID: Study Design IVUS QCA Lipids
*P<0.001 for difference from baseline. Wilcoxon signed rank test Median atheroma volume in the most diseased 10-mm subsegment Median normalized TAV Change from baseline (%) - 9.1% * * - 6.8% End Point Analysis: Change in Key IVUS Parameters n=319 n=346 Adapted from Nissen et al. JAMA 2006;295(13):
Example of Regression of Atherosclerosis with Rosuvastatin in ASTEROID (measured by IVUS) Sipahi I, Nicholls S, Tuzcu E, Nissen S. Interpreting the ASTEROID trial: Coronary atherosclerosis can regress with very intensive statin therapy. Cleve Clin J Med, 2006; 73: Reprinted with permission. Copyright Cleveland Clinic Foundation. All rights reserved.
Diabetes Mellitus: Effect of an HMG-CoA Reductase Inhibitor Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2008;37: Meta-analysis of 18,686 patients with DM randomized to treatment with a HMG-CoA Reductase Inhibitor A statin reduces adverse CV events in diabetics
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
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
Should High-Density Lipoprotein Be a Target of Therapy? Should High-Density Lipoprotein Be a Target of Therapy?
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
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
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
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:
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:
Risk Reduction for CHD Events As a Function of Changes in TC, LDL-C, and HDL-C *4S, CARE, LIPID, WOSCOPS **HELSINKI, VA-HIT,AFCAPS/TexCAPS PERCENT CHD EVENT CHANGE RATE
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
ACCORD Lipid Study Results (NEJM 2010; 362: ) 5518 patients with type 2 DM treated with open label simvastatin randomly assigned to fenofibrate or placebo and followed for 4.7 years. Annual rate of primary outcome of nonfatal MI, stroke or CVD death 2.2% in fenofibrate group vs. 1.6% in placebo group (HR=0.91, p=0.33). Pre-specified subgroup analyses showed possible benefit in men vs. women and those with high triglycerides and low HDL-C. Results support statin therapy alone to reduce CVD risk in high risk type 2 DM patients.
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
Is Niacin Useful in Low HDL-C?
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 ‡
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
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:
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.
Boden WE. N Engl J Med. epub 15 Nov 2011; doi /NEJMoa AIM-HIGH — Results HDL-C at Baseline and Follow-up
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
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 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
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%
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:
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%
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 =
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:
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
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
dal-OUTCOMES Results: HDL STILL Functional Schwartz GG et al. N Engl J Med Nov 5. [Epub ahead of print]. Change in HDL Cholesterol (mg/dL) from Baseline to Month 1, According to Quintile Annualized Event Rate (%)
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
Revisiting the HDL Hypothesis Where do we go Next? Residual CVD risk exists despite intense statin monotherapy Low HDL-C predicts high CVD risk; high HDL-C is protective Existing HDL raising therapies have inconsistent effects Clinical trials have not yet answered the following: Is HDL a causal factor or a biomarker of risk? Does raising HDL-C reduce CVD risk? Investigational drugs to raise HDL-C and reduce CVD risk Continued need for multifactorial approaches to reduce CVD risk
Current Investigational Approaches to Reduce Residual CVD Risk via Enhanced HDL, etc. Additional CETP inhibitors: anacetrapib, evacetrapib Apolipoprotein A1 (Apo A1) Milano; Apo A1 agonist Delipidated HDL; rHDL Selective LXRβ (liver X receptor) agonist DMHCA; GW 3965 PPAR (peroxisome proliferator-activated receptor α/γ agonist aleglitazar, muraglitazar, tesaglitazar DPP-4 (dipeptidyl peptidase-4) antagonist alogliptin, linagliptin, saxagliptin, sitagliptin MTP (microsomal transport protein) antagonist
Effects of Lp-PLA2 inhibition by darapladib in diabetic, hypercholesterolemic pigs Wilensky et al (2008) Nature Medicine (in press) Novel anti-atherosclerotic agents Darapladib in animal models and clinical trials STABILITY Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Estimated enrolment 15,500 Darapladib vs placebo in well treated patients with CHD plus other risk. 1ary endpoint major coronary event SOLID – TIMI52 Stabilization of plaques using darapladib. Incidence of major coronary events in patients with ACS Darapladib 160 mg vs placebo started within 30 days of index ACS event.
NCEP ATP III: Evaluation— Major Risk Factors for CAD Age (men 45 y; women 55 y) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Cigarette smoking Hypertension (BP 140/90 mm Hg or antihypertensive medication) HDL-C <40 mg/dL Family history of premature CAD <55 y in first-degree male relative <65 y in first-degree female relative
Revised ATP III (AHA/NHLBI) Metabolic Syndrome Definition 2005 *Diagnosis is established when 3 of these risk factors are present. † Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡ Some men develop metabolic risk factors when circumference is only marginally increased. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: ; Updated AHA/NHLBI Statement Oct 18, 2005: Grundy et al. Circulation 2005; 112 (epub). <40 mg/dL <50 mg/dL or Rx for ↓ HDL Men Women >102 cm (>40 in) >88 cm (>35 in) Men Women 100 mg/dL or Rx for ↑ glucose Fasting glucose 130/ 85 mm Hg or on HTN Rx Blood pressure HDL-C 150 mg/dL or Rx for ↑ TG TG Abdominal obesity † (Waist circumference ‡ ) Defining Level Risk Factor
NCEP ATP III: Evaluation— Need for Framingham Calculation Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. No>20% CAD or CAD risk equivalent Yes0%-10% 2 RF No<10% 1 RF Need for Framingham Calculation 10-Year Risk for CAD Risk Profile Yes10%-20%
NCEP ATP III: Evaluation— CAD Risk Equivalents Diabetes Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Atherosclerotic disease Peripheral artery disease Abdominal aortic aneurysm Symptomatic carotid artery disease CAD 10-year risk >20%
hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI Total Cholesterol:HDL Ratio Ridker et al, Circulation. 1998;97:2007–2011. hs-CRP Relative Risk
JUPITER Why Consider Statins for Low LDL, high hsCRP Patients? However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses. Ridker et al, New Engl J Med 2001;344: Low LDL, Low hsCRP Low LDL, High hsCRP Statin EffectiveStatin Not Effective [A] [B] Low LDL, Low hsCRP Low LDL, High hsCRP Statin EffectiveStatin Not Effective AFCAPS/TexCAPS Low LDL Subgroups RR
Rosuvastatin 20 mg (N=8901) MIStrokeUnstable Angina Angina CVD Death CABG/PTCA JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP 4-week run-in Ridker et al, Circulation 2003;108: No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L JUPITER Trial Design Placebo (N=8901) Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela
JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI P < Number Needed to Treat (NNT 5 ) = % Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,9018,6318,4126,5403,8931,9581, ,9018,6218,3536,5083,8721,9631, Ridker et al NEJM 2008
JUPITER population – high CRP (>2mg/l), low LDL Dual Target Analysis: LDL-C <70 mg/dL, hsCRP <2 mg/L LDL >70 mg/dL and / or hsCRP >2 mg/L HR 0.64 ( ) LDL <70 mg/dL and hsCRP <2 mg/L HR 0.35 ( ) placebo HR 1.0 (referent) P < Cumulative Incidence Number at Risk Follow-up (years) rosuvastatin placebo 7,7167,6997,6786,0403,6081,8121, ,8327,8067,7776,1143,6561,8631, Ridker PM et al. Lancet 2009;373:1175–1182
1 RF 2 RFs equivalent CAD or CAD risk Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Risk Category <160 <130 <100 <130 LDL-C Goal (mg/dL) 160 130 100 130 LDL-C Level to Initiate TLC (mg/dL) LDL-C Level to Initiate Drug Therapy (mg/dL) 190 160 130 (10-year risk 0%-10%) (10-year risk 10%-20%) NCEP ATP III Guidelines: Treatment
Statins in ACS - Guidelines Who - Initiate therapy regardless of baseline LDL. When – Pre-discharge; but no difference in benefit when initiated immediately or days post event (ESC <4 days). What – Evidence base is for high dose statin (but not 80mg simvastatin). Goal - <70 mg/dl (2.0 mmol/l) LDL cholesterol. ACC/ AHA 2007 in JACC (2008) 51; ESC 2007 in Eur Heart J (2007) 28;
Lipid Management Goal: Persons with Pre-existing CHD LDL-C should be less than 100 mg/dL Further reduction to LDL-C to < 70 mg/dL is reasonable *Non-HDL-C = total cholesterol minus HDL-C If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL*
1 RF<190 2 RFs (CAD risk 20%) <160 CAD or CAD risk equivalent<130 (CAD risk >20%) NCEP ATP III: Setting Goals— Secondary–Non-HDL-C Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Risk CategoryNon–HDL-C Goal (mg/dL) (Patients With TG 200)
Level (mg/dl) Classification <200Desirable Borderline High >240 High Level (mg/dl) Classification>40 Minimum goal* Desired goal* >50High Level (mg/dl) Classification<150Normal Borderline High High >500 Very High Total CholesterolHDL-Cholesterol Triglyceride Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285: ATP III Classification of Other Lipoprotein Levels *These goals apply to men. For women, the minimum goal is >50 mg/dL HDL=High density lipoprotein
NCEP ATP III Guidelines: Treatment Therapeutic Lifestyle Change (TLC) Improve diet Weight reduction Physical activity Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. Pharmacologic Treatment Statins (HMG-CoA reductase inhibitors) Fibrates Niacin Bile acid sequestrants
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
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
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:
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
Moderate physical activity at least minutes 5 days a week or longer will help to raise HDL-C, lower total and LDL-C, lower TG, lower glucose, insulin, and blood pressure levels.
When LDL-lowering drug therapy is employed in high-risk or moderately high risk patients, intensity of therapy should be sufficient to achieve a 30–40% reduction in LDL-C levels.
Effect of Statin Therapy on LDL-C Levels: “The Rule of 6” Illingworth DR. Med Clin North Am. 2000;84:23-42.
Atorvastatin Pravastatin Rosuvastatin Simvastatin 10 mg 20 mg 40 mg 80 mg Dose *P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg **P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg † P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg 1.Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE. *P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg **P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg † P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg 1.Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE. * ** † –60 –50 –40 –30 –20 – Mean Percent Change From Baseline in LDL-C (SE) Percentage Change From Baseline in LDL-C at Week 6 by Dose (ITT) 1,2
Grundy et al. Circulation. 2004;110: Doses of Statins Required to Attain 30-40% Reduction of LDL-C Dose, mg/d LDL Reduction, % Atorvastatin1039 Lovastatin4031 Pravastatin4034 Simvastatin Fluvastatin Rosuvastatin
Source: Kashani A et al. Circulation 2006;114: % incidence of elevated hepatic transaminases (1.1% incidence in control arm) Dose-dependent phenomenon that is usually reversible 15.4% incidence of myalgias* (18.7% incidence in control arm) 0.9% incidence of myositis (0.4% incidence in control arm) 0.2% incidence of rhabdomyolysis (0.1% incidence in control arm) 74,102 subjects in 35 randomized clinical trials with statins *The rate of myalgias leading to discontinuation of atorvastatin in the TNT trial was 4.8% and 4.7% in the 80 mg and 10 mg arms, respectively. HMG-CoA Reductase Inhibitor: Adverse Effects Hepatocyte Skeletal myocyte
Why combination therapy? Few patients achieve LDL-C goal on monotherapy Uptitration of dosage is rare LDL-C goals are getting more aggressive High-dose statins increase risk of side effects Can address mixed dyslipidemia (e.g., few pts achieve adequate control of HDL-C and triglycerides on monotherapy)
Options for Patients who Fail to Reach LDL-C Goal on Statin Monotherapy Niacin Bile acid sequestrant Cholesterol absorption inhibitor Addition of:
Pharmacologic Therapy: Niacin Reduces HDL catabolism and VLDL production Primarily used to treat low HDL-C (15%-35% ) and elevated TG (20%-50% ) LDL-C 5%-25% Side effects Hepatotoxicity, hyperglycemia, hyperuricemia, upper GI distress, flushing, itching Contraindicated in patients with liver disease, gout, peptic ulcer Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
Mean change from Baseline Source: Goldberg A et al. Am J Cardiol 2000;85: HDL-C LDL-C TG –9% –14% –22% –21% –17% 30% 26% 22% 15% 10% –28% –35% –44% –39% –11% –5% Dose (mg)3000 Nicotinic Acid Evidence: Effect on Lipid Parameters HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride
Bile Acid Sequestrants Major actions Reduce LDL-C 15%-30% Raise HDL-C 3%-5% May increase TG Side effects GI distress/constipation Decreased absorption of other drugs (1st generation) Contraindications Dysbetalipoproteinemia Elevated TG (especially >400 mg/dL)
New Bile Acid Sequestrant: Colesevelam Lower dose for effect Fewer GI complaints than with other bile acid sequestrants Reduces absorption of -carotene Requires 4-6 tablets/day Davidson et al. Expert Opin Investig Drugs. 2000;9:2663.
Insull et al. Mayo Clin Proc. 2001;76:971. *P<0.001 vs placebo. † P=0.04 vs placebo. % Change from baseline at wk 24 TG HDL-C LDL-C * † Placebo (n=88) Colesevelam 3.8 g/d (n=95) Colesevelam Monotherapy: Efficacy
Pharmacologic Therapy: Fibrates Inhibit hepatic TG production and increase HDL production Used to treat elevated TG (20%-50% ) and low HDL-C (10%-20% ) Variable effect on LDL-C Side effects Dyspepsia, gallstones, myopathy Increased with statins Contraindicated in patients with severe renal or hepatic disease Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486.
Limitations of Current Intestinal-Acting Agents Bile acid sequestrants Noncompliance GI tolerability Reduced absorption of lipid-soluble vitamins May increase TG in patients with hypertriglyceridemia Plant stanol and sterol esters Lack of selectivity Some patients may find difficult to incorporate into diet May reduce absorption of lipid-soluble vitamins
Ezetimibe — Localizes at Brush Border of Small Intestine Ezetimibe, a selective cholesterol absorption inhibitor, localizes and appears to act at the brush border of the small intestine and inhibits cholesterol absorption This results in A decrease in the delivery of intestinal cholesterol to the liver A reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood
Ezetimibe and Statins Complementary Mechanisms Ezetimibe reduces the delivery of cholesterol to the liver Statins reduce cholesterol synthesis in the liver The distinct mechanism of ezetimibe is complementary to that of statins The effects of ezetimibe, either alone or in addition to a statin, on cardiovascular morbidity or mortality have not been established Knopp RH. N Engl J Med. 1999;341:498–511.
Mean Percent Change in LDL-C From Baseline Placebo (n = 11) SIMVA 10 mg (n = 12) SIMVA 10+ EZE 10 mg (n = 11) -34.9* -51.9*† Coadministration: Simvastatin + Ezetimibe *P < 0.01 vs placebo †P < 0.01 vs simvastatin 10 mg Stein, E. Eur Heart J. 2001;3(suppl E):E14. 17%
% 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
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
-3 Fatty Acids Evidence: Secondary Prevention **p<0.05 -3 Fatty Acids Placebo Source: Burr ML et al. Lancet 1989;2: Diet and Reinfarction Trial (DART) All cause mortality (%) *Corresponds to 2.5 grams of EPA (PUFA) EPA=Eicosapentaenoic acid, MI=Myocardial infarction 2,033 men with a history of a MI randomized to a diet of reduced fat with an increased ratio of polyunsaturated to saturated fat, increased fatty fish intake*, or increased fiber intake for 2 years -3 fatty acids reduce all cause mortality** after a MI
11,324 patients with a history of a MI randomized to -3 polyunsaturated fatty acids [PUFA] (1 gram), vitamin E (300 mg), both or none for 3.5 years -3 fatty acids provide significant CV benefit after a MI Source: GISSI Investigators. Lancet 1999;354: -3 Fatty Acids Evidence: Secondary Prevention Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI-Prevenzione) CV=Cardiovascular, MI=Myocardial infarction, NF=Non- fatal, PUFA=Polyunsaturated fatty acids Percent of patients P=0.048 P=0.053P=0.023P=0.008 stroke Death, NF MI, NF stroke (2 way) CV death, NF MI, and NF Death, NF MI, NF stroke (4 way) CV death, NF MI, and NF -3 PUFA Placebo
3,827 patients 3-14 days following a MI randomized to -3 fatty acids (460 mg EPA mg DHA) or placebo for 1 year -3 fatty acids provide no benefit following a MI in those with high utilization of risk reducing therapies OMEGA Trial Source: Senges J et al. Presented at the Annual Scientific Sessions of the American College of Cardiology, March 2009, Orlando, FL Placebo 8.8 Fatty acids P=0.10 Rate of reinfarction, stroke, or death* (%) DHA=Docosahexaenoic acid, EPA=Eicosapentaenoic acid, MI=Myocardial infarction *This is a secondary endpoint -3 Fatty Acids Evidence: Secondary Prevention
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.