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 Learning Objectives  Discuss the role of cholesterol, lipoproteins, and the metabolic syndrome in coronary heart disease  Examine the results of important cholesterol lowering clinical trials and understand their relevance in clinical practice  Review current NCEP goals for lipid management  Evaluate the efficacy and safety profiles of various cholesterol lowering strategies including diet and lifestyle regimens and pharmacologic agents Most Myocardial Infarctions Are Caused by Low-Grade Stenoses Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, 1992. (Adapted from Falk et al.) Falk E et al, Circulation, 1995. Lipoproteins Water-soluble way to transport hydrophobic lipids • Envelope of phospholipids and free cholesterol • Triglyceride and cholesteryl ester-rich core • Vary in size and density From: Braunwald et al, Heart Disease: A Textbook of Cardiovascular Medicine 6th ed., 2001 Lipoprotein Particles 0.95 VLDL Chylomicron Density (g/ml) VLDL Remnants 1.006 IDL Chylomicron Remnants 1.019 LDL-R 1.050 1.063 1.100 HDL2 Lp(a) HDL3DL3 1.20 Only these lipoprotein particles found in plaque at biopsy. 5 10 20 40 60 80 1000 Particle Size (nm) Lipid Atherogenesis HDL Endothelial injury Adherence of platelets LCAT APO-A1 Release of PDGF Other growth factors High plasma LDL LDL + VLDL LDL infiltration into intima Liver Oxidative modification of LDL + Macrophages Foam cells Fatty streak Cholesterol excreted Advanced fibrocalcific lesion Genetic Causes of Dyslipidemia  Type I – Familial Hyperchylomicronemia  Fasting triglycerides > 1000 mg/dl  Defect in lipoprotein lipase or apo CII  Not necessarily at increased risk of CAD  Type II - Familial Hypercholesterolemia (type II)      LDL-C > 95th percentile for age and gender CAD in men by 3rd or 4th decade Defect in LDL receptor Autosomal dominant inheritance Prevalence 1:500  Familial Defective apo B 100  Defective apo B alters LDLr handling  Previously undetecable from FH 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 AIMilano) Tangier’s Disease CETP defects result in increased HDL ______________________________________________________________ Compliance with Lipid Treatment Guidelines _______________________________________________________________ mg/dL  Less than half those eligible undertake treatment  Only a third of those treated achieve their LDL-C goals  40% of patients surveyed who saw a physician in preceding 2 years were unaware of their lipid status  Only 20-25% of CVD patients in the U.S. are reported to be on treatment for dyslipidemia __________________________________________________________________ AHA Heart Disease and Stroke Statistics: 2004 Update NHANES II Behavioral Risk Factor Survey  About half U.S. population has LDL-C >130 Total Cholesterol Distribution: CHD vs Non-CHD Population Framingham Heart Study—26-Year Follow-up 35% of CHD Occurs in People with TC<200 mg/dL No CHD CHD 150 200 250 300 Total Cholesterol (mg/dL) Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 1996 Reprinted with permission from Elsevier Science. Lipid Parameters and Risk of CAD Over 8 Years (PROCAM) 12 10 LDL-C HDL-C TG Incidence (%) 8 6 4 2 0 <133 133-163 >163 <40 40-49 >49 <105 105-166 >166 mg/dL Assmann et al. Eur Heart J. 1998;19(suppl A):A2. Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal 14 12 10 8 6 4 2 0 14-y incidence rates (%) for CHD < 40 40–49 50–59  60 HDL-C (mg/dL)  260 230–259 200–229 < 200 Risk of CHD by HDL-C and Total-C levels; aged 48–83 y Castelli WP et al. JAMA 1986;256:2835–2838 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;274:1771-1774. Stein JH, Rosenson RS. Arch Intern Med. 1997;157:1170-1176. Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort 10 5 2 RR 1 0.5 Lp(a) TC HDL-C HT 2.7 1.9 1.8 1.8 1.2 GI 3.6 Smoking 0.2 0.1 RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA. 1996;276:544-548. LDL Particle Size Subclass: Fasting triglycerides of 175 mg/dl or greater or TG/HDL ratio >3 is a good surrogate of small, dense LDL particle side IDL L3 large, buoyant L2 L1 small, dense A AB B Accumulation of Other Risk Factors Compound Effects of Dyslipidemia on Risk of CHD 40 35 30 25 20 15 10 5 0 185 210 235 260 285 310 335 Schaefer EJ, adapted from the Framingham Heart Study Low HDL Smoking Hyperglycemia Hypertension No Other Risk Factors Serum Cholesterol (mg/dL) Primary and Secondary Prevention Trials With Statins 1° prevention statin 1° prevention placebo 30 25 Event Rate (%) 4S 20 15 HPS CARE LIPID HPS AFCAPS AFCAPS 80 90 CARE WOSCOPS LIPID 2° prevention statin 2° prevention placebo 4S 10 5 0 WOSCOPS 100 110 120 130 140 150 160 170 180 190 200 LDL-C Achieved (mg/dL) Adapted from Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q. 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  Meta-analysis of Statin Trials 5 LDL-C HDL-C TG Coronary Fatal Total Events CHD Mortality 0 -5 +5 Change (%) -10 -15 -20 -21 -25 -30 -35 -28 -31 -29 -13 LaRosa JC et al. JAMA. 1999;282:2340-2346. Statin Trials: Therapy Reduces Major Coronary Events in Women 10 5 0 -5 -10 -15 % D -20 -25 -30 -35 -40 -45 -50 Major coronary events* -34 P=0.012 -46 AFCAPS/TexCAPS (n=997) 1 Prevention -46 P=0.001 4S (n=827) CARE (n=576) 2 Prevention n = number of women enrolled. * 4S = primarily CHD death and nonfatal MI; CARE = coronary death, nonfatal MI, angioplasty, or bypass surgery; AFCAPS/TexCAPS = fatal/nonfatal MI, unstable angina, or sudden cardiac death. Miettinen TA et al. Circulation. 1997;96:4211-4218. Lewis SJ et al. J Am Coll Cardiol. 1998;32:140-146. Downs JR et al. JAMA. 1998;279:1615-1622. Effects of Statins on Stroke: A Meta-analysis of Primary- and Secondary-Prevention Trials 0 1° Prevention (-42 to -27)† 2° Prevention (13-45)† Combined (11-40)† -10 Relative reduction-20 in rates (%) -30 -15 -27* -32* -40 *P=0.001. †95% confidence interval of percentage of relative reduction. Crouse JR et al. Arch Intern Med. 1997;157:13051310. HPS: First Major Coronary Event StatinPlaceboType of Major Allocated Allocated Vascular Event (n = 10269) (n = 10267) Coronary events Nonfatal MI Coronary death Subtotal: MCE 357 (3.5%) 587 (5.7%) 898 (8.7%) 513 (5.0%) 450 (4.4%) 939 (9.1%) 574 (5.6%) 707 (6.9%) 1212 (11.8%) 725 (7.1%) 532 (5.2%) 1205 (11.7%) 0.76 (0.700.83) P < 0.0001 0.76 (0.720.81) P < 0.0001 0.73 (0.670.79) P < 0.0001 Statin Better Placebo Better Revascularizations Coronary Noncoronary Subtotal: any RV Any MVE 2033 (19.8%) 2585 (25.2%) 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 Baseline LDL-C (mg/dL) <100 100–129 130 All patients Statin (n = 10,269) 282 (16.4%) 668 (18.9%) 1083 (21.6%) 2033 (19.8%) Placebo (n = 10,267) 358 (21.0%) 871 (24.7%) 1356 (26.9%) 2585 (25.2%) Event Rate Ratio (95% CI) Statin Better Statin Worse 0.76 (0.72–0.81) P < 0.0001 0.4 0.6 0.8 1.0 1.2 1.4 www.hpsinfo.org HPS: Incidence of MI and stroke in diabetic patients without prior disease Simvastatin (n=2006) Placebo (n=1976) p value Relative reduction (adjusted) 279 (13.9%) 369 (18.7%) <0.0001 28% Collins R et al. Presented at the American Heart Association Scientific Sessions. November 13, 2001. Collaborative Atorvastatin Diabetes Study (CARDS)  2838 patients aged 40-75 with type 2 diabetes, no prior CVD, but at least 1 of the following: retinopathy, albuminuria, smoking, or hypertension  Randomization to 10 mg atorvastatin or placebo  Mean follow-up 3.9 years  Reduction in all CVD events of 37% (p=0.001), all cause mortality 27% (p=0.059). CHD events reduced 36% and stroke 48%. Colhoun HM et al., The Lancet 2004; 364: 685-696 ASCOT: Primary Endpoint: Nonfatal MI/Fatal CHD 4 Cumulative Incidence (%) Atorvastatin 10 mg Placebo Number of events Number of events 100 154 3 36% reduction 2 1 HR = 0.64 (0.50-0.83) 0 P = 0.0005 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158. TNT: Rationale 30 Patients With CHD Events (%) 25 20 15 10 5 0 60 (1.6) 80 (2.1) 100 (2.6) ? TNT Screening Atorvastatin 10 mg Atorvastatin 80 mg 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) 200 (5.2) LDL-C, mg/dL (mmol/L) Adapted from LaRosa et al. N Engl J Med. 2005:352:1425-1435. TNT: Changes in LDL-C by Treatment Group 160 140 Baseline Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) 4.0 3.5 Mean LDL-C (mmol/L) Mean LDL-C (mg/dL) 120 100 80 60 40 20 0 Mean LDL-C level = 101 mg/dL (2.6 mmol/L) 3.0 2.5 2.0 P<.001 Mean LDL-C level = 77 mg/dL (2.0 mmol/L) 1.5 1.0 0.5 0 Screen 0 3 12 24 36 48 Study Visit (Months) 60 Final LaRosa et al. N Engl J Med. 2005;352:1425-1435. TNT: Primary Efficacy Outcome Measure: Major Cardiovascular Events* Proportion of Patients Experiencing Major Cardiovascular Event 0.15 Atorvastatin 10 mg Atorvastatin 80 mg 0.10 Mean LDL-C level = 101 mg/dL Relative risk reduction 22% 0.05 Mean LDL-C level = 77 mg/dL HR=0.78 (95% CI 0.69, 0.89); P<.001 0 0 1 2 3 Time (Years) 4 5 6 * CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. LaRosa et al. N Engl J Med. 2005;352:1425-1430. Are LDL and HDL Effects Additive? 2nd Order Relationship % Absolute Change in LDL+HDL 0 10 20 BIP 30 40 ALLHAT 50 60 70 80 0 % CV Event RRR 20 VA HIT DAIS CDP LIPID HHS WOSCOPS PROSPER CARE, HPS 4S AFCAPS/ TexCAPS FATS F/U 40 60 80 ASCOT R2 = 0.8512 100 HATS FATS HATS: Percent Change in Stenosis 4.5 4.0 3.5 Change (%) 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 Placebo Antioxidant Vitamins* Simvastatin/ Niacin† Simvastatin / Niacin/ Antioxidants‡ *P = 0.16 for comparison with placebo; †P < 0.001; ‡P = 0.004. HATS = HDL-Atherosclerosis Treatment Study. Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592. HATS: Patients Free of Events Patients Free of Events (%) 100 Simvastatin-niacin 97% 90 80 All placebos 76% 70 0 RR = 0.10 P = 0.03 0 1 2 3 Years HATS = HDL-Atherosclerosis Treatment Study. Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592. ARBITER 2: Primary Endpoint Carotid IMT Across 12 Months 0.07 0.06 Change in CIMT (mm +/- SEM) 0.05 0.04 0.03 0.02 0.01 0 ER Niacin Placebo D CIMT at 12 months 68% decrease in progression • Statin vs ER niacin + statin P = 0.08 • Intent-to-treat analysis of statin vs. ER niacin + statin P = 0.048 • Non-Insulin resistant pts only: statin vs. ER niacin P = 0.026 Taylor AJ, et al. ARBITER 2: A double-blind, placebo-controlled study of extended-release niacin on Atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004 How low to go? Recent Findings from PROVE-IT and REVERSAL  PROVE-IT (Cannon CP et al., NEJM 2004; 350: 1495-1504)  randomized 4162 ACS pts to 80 mg atorvastatin vs. 40 mg pravastatin  median on-treatment LDL-C of 62 mg/dl vs. 95 mg/dl.  16% reduction of combined death, MI, unstable angina req. hosp., stroke, and revas in 30 days on atorvastatin  REVERSAL (Nissen SE et al., JAMA 2004; 291: 1071-80)  randomized 654 pts to atorvastatin 80 mg vs. pravastatin 40 mg; 502 and evaluable IVUS at baseline and after 18 mos on treatment.  On-treatment LDL-C 79 mg/dl on atorvastatin and 110 mg/dl on pravastatin.  Those on atorvastatin showed significantly less progression of atheroma volume Late Breaking Clinical Trial, ACC 3/8/05 Treating to New Targets (TNT) Study  10,001 pts with CAD randomized to 10 mg atorvastatin (n=5006) vs. 80m mg atorvastatin (n=4995) for 4.9 years, reducing LDL-C to 101 mg/dl and 77 mg/dl, respectively  Total major cardiovascular events were 10.9% on low dose atorvastatin vs. 8.7% on high dose atorvastatin, representing a 22% reduction in risk  Provides evidence that treatment to a lower target below the recommended 100 mg/dl goal will provide additional benefit in preventing cardiovascular events N Engl J Med, 3/8/05 NCEP ATP III: Evaluation— Major Risk Factors for CAD Age (men 45 y; women 55 y) Cigarette smoking Hypertension (BP 140/90 mm Hg or antihypertensive medication) HDL-C <40 mg/dL Family history of premature CAD  <55 y in first-degree male relative  <65 y in first-degree female relative Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. NCEP ATP III: Evaluation— CAD Risk Equivalents Diabetes Atherosclerotic disease  Peripheral artery disease  Abdominal aortic aneurysm  Symptomatic carotid artery disease CAD 10-year risk >20% Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. NCEP ATP III: Evaluation— Need for Framingham Calculation 10-Year Risk for CAD <10% 0%-10% 10%-20% Need for Framingham Calculation No Yes Yes No Risk Profile 1 RF 2 RF CAD or CAD risk equivalent >20% Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. ATP III Framingham Risk Scoring Assessing CHD Risk in Men Step 1: Age Years 20-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 Points -9 -4 0 3 6 8 10 11 12 13 Step 4: Systolic Blood Pressure Systolic BP (mm Hg) <120 120-129 130-139 140-159 160 Points Points if Untreated if Treated 0 0 0 1 1 2 1 2 2 3 Step 6: Adding Up the Points Age Total cholesterol HDL-cholesterol Systolic blood pressure Smoking status Point total Point Total 10-Year 11 12 13 14 15 16 17 8% 10% 12% 16% 20% 25% 30% Step 2: Total Cholesterol TC Points at at Points at (mg/dL) Age 20-39 70-79 <160 0 160-199 4 200-239 7 240-279 9 280 11 Step 3: HDL-Cholesterol HDL-C (mg/dL) 60 50-59 40-49 <40 Points -1 0 1 2 Points at Points at Points Age 40-49 Age 50-59 Age 60-69 Age 0 3 5 6 8 0 2 3 4 5 Points at Points at Age 20-39 0 8 0 1 1 2 3 Points at 0 0 0 1 1 Step 5: Smoking Status at 70-79 Nonsmoker Smoker Step 7: CHD Risk Point Total 10-Year Risk Risk <0 <1% 0 1% 1 1% 2 1% 3 1% 4 1% 5 2% 6 2% 7 3% 8 4% 9 5% 10 6% Points at Points Age 40-49 Age 50-59 Age 60-69 Age 0 5 0 3 0 1 0 1 Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. © 2001, Professional Postgraduate Services® www.lipidhealth.org ATP III Framingham Risk Scoring Assessing CHD Risk in Women Step 1: Age Years 20-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 Points -7 -3 0 3 6 8 10 12 14 16 Step 4: Systolic Blood Pressure Systolic BP (mm Hg) <120 120-129 130-139 140-159 160 Points Points if Untreated if Treated 0 0 1 3 2 4 3 5 4 6 Step 6: Adding Up the Points Age Total cholesterol HDL-cholesterol Systolic blood pressure Smoking status Point total Step 7: CHD Risk Point Total 10-Year Risk Risk <9 <1% 9 1% 10 1% 11 1% 12 1% 13 2% 14 2% 15 3% 16 4% 17 5% 18 6% 19 8% Points at Points Point Total 10-Year 20 21 22 23 24 25 11% 14% 17% 22% 27% 30% Step 2: Total Cholesterol TC Points at at Points at (mg/dL) Age 20-39 70-79 <160 0 160-199 4 200-239 8 240-279 11 13 Step 280 3: HDL-Cholesterol HDL-C (mg/dL) 60 50-59 40-49 <40 Points -1 0 1 2 Points at Points at Points Age 40-49 Age 50-59 Age 60-69 Age 0 3 6 8 10 0 2 4 5 7 0 1 2 3 4 0 1 1 2 2 Step 5: Smoking Status at Points at Points at Age 20-39 Points at 7 4 Note: Risk estimates were derived the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. 70-79 Nonsmoker 0 Smoker from the experience9of Age 40-49 Age 50-59 Age 60-69 Age 0 0 0 2 0 1 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. © 2001, Professional Postgraduate Services® www.lipidhealth.org NCEP ATP III Guidelines: Treatment Risk Category  1 RF  2 RFs CAD or CAD risk equivalent (10-year risk 0%-10%) (10-year risk 10%-20%) LDL-C Level LDL-C LDL-C Level to Initiate Goal to Initiate Drug Therapy (mg/dL) TLC (mg/dL) (mg/dL) <160 <130 <130 160 130 130 190 160 130 <100 100 130 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. NCEP ATP III: Setting Goals— Secondary–Non-HDL-C (Patients With TG 200) Risk Category 1 RF 2 RFs (CAD risk 20%) CAD or CAD risk equivalent (CAD risk >20%) Non–HDL-C Goal (mg/dL) <190 <160 <130 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. NCEP ATP III Guidelines: Treatment Therapeutic Lifestyle Change (TLC) Improve diet Weight reduction Pharmacologic Treatment Statins (HMG-CoA reductase inhibitors) Fibrates Niacin Bile acid sequestrants Physical activity Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486. I have some bad news for you. While your cholesterol has remained the same, the research findings have changed. Lipid Management Goal I IIa IIb III LDL-C should be less than 100 mg/dL I IIa IIb III Further reduction to LDL-C to < 70 mg/dL is reasonable If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL* *Non-HDL-C = total cholesterol minus HDL-C Lipid Management Goals: NCEP Consider Drug Therapy Risk Category LDL-C and non-HDLC Goal <100 mg/dL if TG > 200 mg/dL, non-HDL-C should be < 130 mg/dL <70 mg/dL, non-HDL-C < 100 mg/dL Initiate TLC High risk: CHD or CHD risk equivalents (10-year risk >20%) and Very high risk: ACS or established CHD plus: multiple major risk factors (especially diabetes) or severe and poorly controlled risk factors 100 mg/dL >100 mg/dL (<100 mg/dL: consider drug options) All patients >100 mg/dL (<100 mg/dL: consider drug options) ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes Grundy, S. et al. Circulation 2004;110:227-39. Lipid Management Recommendations For all patients I IIa IIb III 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 I IIa IIb III Lipid Management Recommendations Assess fasting lipid profile in all patients, and within 24 hours of hospitalization for those with an acute event. For patients hospitalized, initiate lipid-lowering medication as recommended below prior to discharge according to the following schedule: I IIa IIb III If baseline LDL-C > 100 mg/dL, initiate LDL-lowering drug therapy I IIa IIb III If on-treatment LDL-C > 100 mg/dL, intensify LDLlowering drug therapy (may require LDL lowering drug combination) If baseline is LDL-C 70 to 100 mg/dL, it is reasonable to treat to LDL < 70 mg/dL I IIa IIb III When LDL lowering medications are used, obtain at least a 30-40% reduction in LDL-C levels. Lipid Management Recommendations I IIa IIb III If TG are 200-499 mg/dL, non-HDL-C should be < 130 mg/dL I IIa IIb III Further reduction of non-HDL to < 100 mg/dL is reasonable Therapeutic options to reduce non-HDL-C: More intense LDL-C lowering therapy I (B) or Niacin (after LDL-C lowering therapy) IIa (B) or Fibrate (after LDL-C lowering therapy) IIa (B) If TG are > 500 mg/dL, therapeutic options to prevent I IIa IIb III pancreatitis are fibrate or niacin before LDL lowering therapy; and treat LDL-C to goal after TG-lowering therapy. Achieve non-HDL-C < 130 mg/dL, if possible HMG-CoA Reductase Inhibitor: Secondary Prevention Heart Protection Study (HPS) 20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 years Baseline LDL-C (mg/dL) <100 100–129 130 All patients Statin (n = 10,269) 282 (16.4%) 668 (18.9%) 1083 (21.6%) 2033 (19.8%) Placebo (n = 10,267) 358 (21.0%) 871 (24.7%) 1356 (26.9%) 2585 (25.2%) Event Rate Ratio (95% CI) Statin Better Statin Worse 0.76 (0.72–0.81) P<0.0001 0.4 0.6 0.8 1.0 1.2 1.4 CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus, HPS Collaborative Group. Lancet 2002;360:7-22 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 30 25 20 15 10 5 0 Recurrent MI or Cardiac Death Atorvastatin Pravastatin 16% RRR P =0.005 3 6 9 12 15 18 21 24 27 30 Follow-up (months) ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Cannon CP et al. NEJM 2004;350:1495-1504 HMG-CoA Reductase Inhibitor: Secondary Prevention Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD 30 25 Statin Placebo 4S LIPID LIPID 4S Event (%) 20 15 CARE 10 5 0 0 70 HPS CARE HPS TNT (atorvastatin 10 mg/d) TNT (atorvastatin 80 mg/d) 90 110 130 150 LDL-C (mg/dL) 170 190 210 LDL-C=Low density lipoprotein cholesterol; TNT=Treating to New Targets; HPS=Heart Protection Study; CARE=Cholesterol and Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study. LaRosa JC et al. NEJM. 2005;352:1425-1435 Therapeutic Lifestyle Changes in LDL-Lowering Therapy: Major Features  Saturated fats <7% of total calories  Dietary cholesterol <200 mg per day  Plant stanols/sterols (2 g per day)  Viscous (soluble) fiber (10–25 g per day)  Weight reduction  Increased physical activity Plant Sterol and Stanol Esters Low absorption Reduce LDL-C by 10%-15% May interfere with absorption of lipid-soluble vitamins Plant stanol esters  Saturated derivatives of plant sterol esters  Very low absorption Nguyen. J Nutr. 1999;129:2109. Therapeutic Lifestyle Changes Nutrient Composition of TLC Diet Nutrient Recommended Intake Less than 7% of total calories          Saturated fat Polyunsaturated fat Monounsaturated fat Total fat Carbohydrate Fiber Protein Cholesterol Up to 10% of total calories Up to 20% of total calories 25–35% of total calories 50–60% of total calories 20–30 grams per day Approximately 15% of total calories Less than 200 mg/day Total calories (energy) Balance energy intake and expenditure to maintain desirable body weight Effect of Mediterranean-style diet in the metabolic syndrome  180 pts with metabolic syndrome randomized to Mediterranean-style vs. prudent diet for 2 years  Those in intervention group lost more weight (-4kg) than those in the control group (+0.6kg) (p<0.01), and significant reductions in CRP and Il-6.  After 2 years, 40 pts in intervention group still had features of metabolic syndrome compared to 78 pts in the control group Esposito K et al. JAMA 2004; 292(12): 1440-6. Dietary Approaches to Stop Hypertension (DASH)  Diet high in fruits and vegetables and low-fat dairy products lowers blood pressure more than a sodium-restricted diet  7-8 servings/day of grain/grain products, 4-5 vegetable, 4-5 fruit, 2-3 low- or non-fat dairy products, 2 or less meat, poultry, and fish.  NEJM 1997; 366: 1117-24. Comparison of Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial  160 subjects randomized, 40 to each diet, for 2 months of maximum adherence, and self-selected adherence for rest of year  After 1 year, mean wt loss 2.1 kg for Atkins, 3.2 kg for Zone, 3.0 kg for Weight Watchers, and 3.3 kg for Ornish. Dansinger et al., JAMA 2005; 293: 43-53. Comparison of diets (cont.)  53% completed Atkins, 65% Zone, 65% Weight Watchers, and 50% Ornish  Each diet significantly reduced LDL-C/HDL-C ratio by about 10%, no sig effects on blood pressure or glucose.  Weight loss related to self-reported dietary adherence or type of diet; decreases in total/HDL-C, CRP, and insulin significantly related to weight loss 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)  LDL-C 1% to 10%  LDL-C 5% to 7% • Stanol esters (1.5–4 g/d) (inhibit cholesterol absorption) • Fish oils (3–9 g/d) (n-3 fatty acids) Jones PJ. Curr Atheroscler Rep. 1999;1:230-235. Lichtenstein AH. Curr Atheroscler Rep. 1999;1:210-214. Rambjor GS et al. Lipids. 1996;31:S45-S49. Ripsin CM et al. JAMA. 1992;267:3317-3325.  LDL-C 10% to 15%  Triglycerides 25% to 35% Dietary Adjuncts  TLC for patients with LDL-C = 160 Dietary Component Low saturated fat/dietary cholesterol Viscous fiber (10–25 g/d) Plant stanols/sterols (2 g/d) LDL-C  (mg/dL) –12 –8 –16 Total –36 mg/dl Walden CE et al. Arterioscler Thromb Vasc Biol 1997;17:375-382. Jenkins DJ et al. Curr Opin Lipidol 2000;11:49-56. Cato N. Stanol meta-analysis. Personal communication, 2000. A Model of Steps in Therapeutic Lifestyle Changes (TLC) Visit 2 Visit I Begin Lifestyle Therapies Evaluate LDL 6 wks response If LDL goal not achieved, intensify LDL-Lowering Tx Visit 3 Evaluate LDL Visit N 6 wks response Q 4-6 mo Monitor If LDL goal not Adherence achieved, consider to TLC adding drug Tx • Emphasize reduction in saturated fat & cholesterol • Encourage moderate physical activity • Reinforce reduction in saturated fat and cholesterol • Consider adding plant stanols/sterols • Initiate Tx for Metabolic Syndrome • Intensify weight management & physical activity • Consider referral to a dietitian • Increase fiber intake • Consider referral to • Consider referral to a dietitian a dietitian Factors Influencing Noncompliance Number of daily doses and medications Occurrence and severity of side effects Incompatibility with patients’ daily routine Inadequate physician-patient communication Cost Effect of Lipid-modifying Therapies Therapy Bile acid sequestrants Nicotinic acid Fibrates (gemfibrozil) Statins* TC  7-10%  10-20%  19%  19-37% LDL  10-18%  10-20%  4-21%  25-50% HDL 3%  14-35% 11-13%  4-12% TG Neutral or   30-70%  30%  14-29% Patient tolerability Poor Poor to reasonable Good Good Ezetimibe  13%  18%  1%  9% Good TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin. Questran® Prescribing Information, Colestid ® Prescribing Information, WelChol ® Prescribing information, Niaspan ® Prescribing Information, Lopid ® Prescribing Information, TriCor ® Prescribing Information, Lipitor ® Prescribing Information, Zocor ® Prescribing Information, Mevaco ® r Prescribing Information, Lescol ® Prescribing Information, Pravacol ® Prescribing Information; Zetia ® Prescribing Information. 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. 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. Drug Therapy HMG CoA Reductase Inhibitors (Statins)  Reduce LDL-C 18–55% & TG 7–30%  Raise HDL-C 5–15%  Major side effects  Myopathy  Increased liver enzymes  Contraindications  Absolute: liver disease  Relative: use with certain drugs Effect of Statin Therapy on LDL-C Levels: ―The Rule of 6‖ Lovastatin 20/80 Pravastatin 20/40 Simvastatin 20/80 Fluvastatin 20/80 Atorvastatin 10/80 0 10 19 28 27 35 12 37 6 12 Starting dose LDL-C Highest recommended dose 12 18 20 30 40 50 60 Reduction of LDL Cholesterol (%) Illingworth DR. Med Clin North Am. 2000;84:23-42. Percentage Change From Baseline in LDL-C at Week 6 by Dose (ITT)1,2 Dose Mean Percent Change From Baseline in LDL-C (SE) 0 –10 –20 –30 –40 * 10 mg 20 mg 40 mg 80 mg Rosuvastatin Atorvastatin Simvastatin Pravastatin –50 –60 ** † *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: 152-160. 2.Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE. 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. Doses of Statins Required to Attain 30-40% Reduction of LDL-C Dose, mg/d LDL Reduction, % Atorvastatin Lovastatin Pravastatin Simvastatin 10 40 40 20-40 39 31 34 35-41 Fluvastatin Rosuvastatin 40-80 5-10 25-35 39-45 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 Addition of: • Niacin • Bile acid sequestrant • Cholesterol absorption inhibitor Combination Therapy With IntestinalActing Agents and Statins: Rationale Statins inhibit compensatory increase in cholesterol synthesis induced by blockade of cholesterol absorption May increase ability to reach LDL-C goals May allow use of a lower statin dose 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. Colesevelam Monotherapy: Efficacy LDL-C TG 10 † % Change from baseline at wk 24 15 10 5 0 -5 -10 -15 -20 HDL-C 5 3 0 -1 -15 Placebo (n=88) Colesevelam 3.8 g/d (n=95) * *P<0.001 vs placebo. †P=0.04 vs placebo. Insull et al. Mayo Clin Proc. 2001;76:971. 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. Coadministration: Simvastatin + Ezetimibe Placebo (n = 11) SIMVA 10 mg (n = 12) SIMVA 10+ EZE 10 mg (n = 11) 0 Mean Percent Change in LDL-C From Baseline -10 -20 -30 -40 -50 -60 -3.2 -34.9* *P < 0.01 vs placebo †P < 0.01 vs simvastatin 10 mg 17% -51.9*† Stein, E. Eur Heart J. 2001;3(suppl E):E14. ENHANCE Background Patients with FH have a greatly increased risk of developing premature coronary artery disease and an increased rate of progression of intima-media thickness (IMT) Primary Outcome: change in the carotid IMT, an average of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries Secondary Outcomes: regression in mean carotid IMT, new plaque formation, and various individual measurements of the carotid artery Kastelien J. N Engl J Med. 2008; 358: 1431- 43. ENHANCE Study Design R A N D O M I Z A T I O N Pre-randomization Phase FH: LDL-c ≥ 210 mg/dL Ezetimibe 10 mg-Simvastatin 80 mg mg Ezetimibe 10 mg-Simvastatin 80 Screening and Fibrate Washout Placebo LeadIn/ Drug Washout Simvastatin 80 mg Simvastatin 80 mg IMT assessment N = 720 -10 to -7 Weeks -6 0 3 6 9 12 Months 15 18 21 24 Kastelien J. N Engl J Med. 2008; 358: 1431- 43. ENHANCE LDL Changes 10 0 Percentage change from baseline Simva Eze-Simva Baseline (mg/dL) 318 + 66 319 + 65 24 Months (mg/dL) 193 + 60 141 + 53 -10 -20 -30 -40 -50 -60 -70 P<0.01 Simvastatin Eze-Simva -16.5 % incremental reduction in LDL 0 6 12 Months 18 24 Kastelien J. N Engl J Med. 2008; 358: 1431- 43. ENHANCE Primary Outcome : Mean cIMT Mean intima-media thickness of carotid artery (mm) Mean cIMT, baseline Mean cIMT, 24 mo Change from baseline (mm) Simvastatin monotherapy (n=342) 0.70±0.13 0.70±0.14 0.0058±0.003 7 Simvastatin plus ezetimibe (n=338) 0.69±0.13 0.71±0.15 0.0111±0.0038 P value 0.64 0.29 0.29 Kastelien J. N Engl J Med. 2008; 358: 1431- 43. ENHANCE Mean cIMT during 24 months of therapy Longitudinal, repeated measures analysis 0.80 Simvastatin Eze-Simva 0.75 Mean cIMT (mm) P=0.88 0.70 0.65 0.60 6 12 Months 18 24 Kastelien J. N Engl J Med. 2008; 358: 1431- 43. ENHANCE Conclusion Despite the observed improvements in lipid parameters, there were no significant differences in the change in carotid IMT between ezetimibe/simvastatin and simvastatin alone. Reason(s) for this discrepancy currently remains unknown, however: 1. Measurement technique may not be accurate enough to reflect changes in atherosclerotic burden 2. Ezetimibe lacks vascular benefit despite the observed LDL-c and hsCRP reduction 3. The population studied may have been at too low a risk to detect changes, limiting the ability to detect a differential response Kastelien J. N Engl J Med. 2008; 358: 1431- 43.