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 150 200 Total Cholesterol (mg/dL) 250 300 No CHD CHD Framingham Heart Study—26-Year Follow-up
Lipid Parameters and Risk of CAD Over 8 Years (PROCAM) Incidence (%) >49 40-49 <40 <133 133-163 >163 <105 105-166 >166 HDL-C LDL-C TG Assmann et al. Eur Heart J . 1998;19(suppl A):A2. mg/ dL
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;256:2835–2838 0 2 4 6 8 10 12 14 < 40 40–49 50–59 60 < 200 230–259 200–229 260 HDL-C (mg/dL) Total-C (mg/dL) 14-y incidence rates (%) for CHD 11.24 11.91 12.50 11.91 6.56 4.67 9.05 5.53 4.85 4.15 3.77 2.78 2.06 3.83 10.7 6.6
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 RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA . 1996;276:544-548. 1.9 1.8 1.8 1.2 2.7 3.6 RR 0.1 1 10 2 5 0.2 0.5 Lp(a) TC HDL-C HT GI Smoking
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 L2 L1 large, buoyant small, dense A B AB
Accumulation of Other Risk Factors Compound Effects of Dyslipidemia on Risk of CHD Low HDL Smoking Hyperglycemia Hypertension No Other Risk Factors Schaefer EJ, adapted from the Framingham Heart Study CHD Risk Per 1000 (in 6 years) Serum Cholesterol (mg/dL)
Primary and Secondary Prevention Trials With Statins Adapted from Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q . 2° prevention placebo 2° prevention statin 1° prevention placebo 1° prevention statin 0 5 10 15 20 25 30 80 90 100 110 120 130 140 150 160 170 180 190 200 LDL-C Achieved (mg/dL) AFCAPS AFCAPS WOSCOPS WOSCOPS CARE CARE LIPID LIPID 4S 4S Event Rate (%) HPS HPS
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
Statin Trials: Therapy Reduces Major Coronary Events in Women 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. 4S (n=827) CARE (n=576) AFCAPS/TexCAPS (n=997) 2 Prevention 1 Prevention -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 10 Major coronary events* -34 -46 -46 % P =0.012 P =0.001
Effects of Statins on Stroke: A Meta-analysis of Primary- and Secondary-Prevention Trials Crouse JR et al. Arch Intern Med. 1997;157:1305-1310. * P =0.001. † 95% confidence interval of percentage of relative reduction. Relative reduction in rates (%) 1° Prevention (-42 to -27) † 2° Prevention (13-45) † Combined (11-40) †
HPS: First Major Coronary Event 0.4 0.6 0.8 1.0 1.2 1.4 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 < 0.0001 0.76 (0.70 0.83) P < 0.0001 0 .76 (0.72 0.81) P < 0.0001 Statin Better Placebo Better Heart Protection Study Collaborative Group . Lancet. 2002;360:7 22.
HPS: Incidence of MI and stroke in diabetic patients without prior disease Collins R et al. Presented at the American Heart Association Scientific Sessions. November 13, 2001. <0.0001 p value 369 (18.7%) Placebo (n=1976) 28% Relative reduction (adjusted) 279 (13.9%) Simvastatin (n=2006)
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 Sever PS et al, for the ASCOT Investigators. Lancet . 2003;361:1149-1158. 0 1 2 3 4 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Cumulative Incidence (%) 36% reduction HR = 0.64 (0.50-0.83) Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 P = 0.0005
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. 2005:352:1425-1435. LDL-C, mg/dL (mmol/L) Patients With CHD Events (%)
TNT: Changes in LDL-C by Treatment Group Final Screen 0 3 12 24 36 48 60 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;352:1425-1435. Mean LDL-C (mg/dL) Study Visit (Months) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0
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;352:1425-1430. HR=0.78 (95% CI 0.69, 0.89); P <.001 Proportion of Patients Experiencing Major Cardiovascular Event 0 0.05 0.10 0.15 Atorvastatin 10 mg Atorvastatin 80 mg Relative risk reduction 22% 0 1 2 3 4 5 6 Time (Years) Mean LDL-C level = 77 mg/dL Mean LDL-C level = 101 mg/dL
Are LDL and HDL Effects Additive? R2 = 0.8512 0 20 40 60 80 100 0 10 20 30 40 50 60 70 80 % Absolute Change in LDL+HDL % CV Event RRR 4S VA HIT DAIS BIP AFCAPS/ TexCAPS WOSCOPS LIPID CARE, HPS HHS CDP ASCOT ALLHAT PROSPER 2 nd Order Relationship HATS FATS FATS F/U
HATS: Percent Change in Stenosis -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Change (%) * 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. Placebo Antioxidant Simvastatin/ Simvastatin / Vitamins* Niacin † Niacin/ Antioxidants ‡
Simvastatin-niacin 97% All placebos 76% RR = 0.10 P = 0.03 0 1 2 3 0 70 80 90 100 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 (%) Years
ARBITER 2: Primary Endpoint Carotid IMT Across 12 Months
CIMT at 12 months
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 68% decrease in progression 0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Change in CIMT (mm +/- SEM) ER Niacin Placebo
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)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486.
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
NCEP ATP III: Evaluation— CAD Risk Equivalents
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486.
Peripheral artery disease
Abdominal aortic aneurysm
Symptomatic carotid artery disease
CAD 10-year risk >20%
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 Yes 0%-10% 2 RF No <10% 1 RF Need for Framingham Calculation 10-Year Risk for CAD Risk Profile Yes 10%-20%
NCEP ATP III Guidelines: Treatment 1 RF 2 RFs equivalent CAD risk Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486. Risk Category (10-year risk 0%-10%) (10-year risk 10%-20%) CAD or <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) 190 160 130 130
NCEP ATP III: Setting Goals— Secondary – Non-HDL-C 1 RF <190 2 RFs (CAD risk 20%) <160 CAD or CAD risk equivalent <130 (CAD risk >20%) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA . 2001;285:2486. Risk Category Non–HDL-C Goal (mg/dL) (Patients With TG 200)
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
I have some bad news for you. While your cholesterol has remained the same, the research findings have changed.
Lipid Management Goal 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* I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
Grundy, S. et al. Circulation 2004;110:227-39. Lipid Management Goals: NCEP ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes > 100 mg/dL (<100 mg/dL: consider drug options) 100 mg/dL <100 mg/dL if TG > 200 mg/dL, non-HDL-C should be < 130 mg/dL High risk: CHD or CHD risk equivalents (10-year risk >20%) and All patients Initiate TLC > 100 mg/dL (<100 mg/dL: consider drug options) Consider Drug Therapy <70 mg/dL, non-HDL-C < 100 mg/dL LDL-C and non-HDL-C Goal Risk Category Very high risk: ACS or established CHD plus: multiple major risk factors (especially diabetes) or severe and poorly controlled risk factors
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 I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
Lipid Management Recommendations If baseline LDL-C > 100 mg/dL, initiate LDL-lowering drug therapy If on-treatment LDL-C > 100 mg/dL, intensify LDL-lowering 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 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: When LDL lowering medications are used, obtain at least a 30-40% reduction in LDL-C levels. I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
Lipid Management Recommendations If TG are 200-499 mg/dL, non-HDL-C should be < 130 mg/dL 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 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 I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
Event Rate Ratio (95% CI) Statin Better Statin Worse 0.76 (0.72 –0.81) P<0.0001 Heart Protection Study (HPS) HMG-CoA Reductase Inhibitor: Secondary Prevention 20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 years CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus, HPS Collaborative Group. Lancet 2002;360:7-22 358 (21.0%) 282 (16.4%) <100 871 (24.7%) 668 (18.9%) 100–129 2585 (25.2%) 2033 (19.8%) All patients 1356 (26.9%) 1083 (21.6%) 130 Placebo (n = 10,267) Statin (n = 10,269) Baseline LDL-C (mg/dL) 0.4 0.6 0.8 1.0 1.2 1.4
Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study 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 4,162 patients with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months 3 6 9 12 15 18 21 24 27 30 Follow-up (months) 30 25 20 15 10 5 0 P =0.005 Recurrent MI or Cardiac Death 16% RRR Atorvastatin Pravastatin
LaRosa JC et al. NEJM. 2005;352:1425-1435 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. Statin Placebo Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD HMG-CoA Reductase Inhibitor: Secondary Prevention 30 25 20 15 10 5 0 0 70 90 110 130 150 170 190 210 LDL-C (mg/dL) TNT (atorvastatin 80 mg/d) TNT (atorvastatin 10 mg/d) HPS CARE LIPID LIPID CARE HPS Event (%) 4S 4S
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)
Increased physical activity
Plant Sterol and Stanol Esters
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
Saturated fat Less than 7% of total calories
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
Total fat 25–35% of total calories
Carbohydrate 50–60% of total calories
Fiber 20–30 grams per day
Protein Approximately 15% of total calories
Cholesterol Less than 200 mg/day
Total calories (energy) Balance energy intake and expenditure to maintain desirable body weight
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.
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;1:230-235. 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.
TLC for patients with LDL-C = 160
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. – 36 mg/dl Total – 16 Plant stanols/sterols (2 g/d) – 8 Viscous fiber (10–25 g/d) – 12 Low saturated fat/dietary cholesterol LDL-C (mg/dL) Dietary Component
A Model of Steps in Therapeutic Lifestyle Changes (TLC)
Reinforce reduction in saturated fat and cholesterol
Consider adding plant stanols/sterols
Increase fiber intake
Consider referral to a dietitian
Initiate Tx for Metabolic Syndrome
Intensify weight management & physical activity
Consider referral to a dietitian
6 wks 6 wks Q 4-6 mo
Emphasize reduction in saturated fat & cholesterol
Encourage moderate physical activity
Consider referral to a dietitian
Monitor Adherence to TLC Visit N Visit I Begin Lifestyle Therapies Visit 2 Evaluate LDL response If LDL goal not achieved, intensify LDL-Lowering Tx Visit 3 Evaluate LDL response If LDL goal not achieved, consider adding drug Tx
Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160.
Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.
* ** † Mean Percent Change From Baseline in LDL-C ( SE) Pravastatin Simvastatin – 60 – 50 – 40 – 30 – 20 – 10 0
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.
Grundy et al. Circulation. 2004;110:227-239. Doses of Statins Required to Attain 30-40% Reduction of LDL-C 39 10 Atorvastatin 39-45 5-10 Rosuvastatin 25-35 40-80 Fluvastatin 35-41 20-40 Simvastatin 34 40 Pravastatin 31 40 Lovastatin LDL Reduction, % Dose, mg/d
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
Bile acid sequestrant
Cholesterol absorption inhibitor
Combination Therapy With Intestinal- Acting 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
Reduce LDL-C 15%-30%
Raise HDL-C 3% -5%
May increase TG
Decreased absorption of other drugs (1st generation)
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 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)
Limitations of Current Intestinal-Acting Agents
Bile acid sequestrants
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 Mean Percent Change in LDL-C From Baseline Placebo (n = 11) -30 -20 -10 0 SIMVA 10 mg (n = 12) SIMVA 10+ EZE 10 mg (n = 11) -34.9* -51.9*† -3.2 -40 -50 -60 * P < 0.01 vs placebo † P < 0.01 vs simvastatin 10 mg Stein, E. Eur Heart J. 2001;3(suppl E):E14. 17%
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 RANDOMI ZAT I ON 0 24 Months 3 6 9 12 15 18 21 Pre-randomization Phase FH: LDL-c ≥ 210 mg/dL Screening and Fibrate Washout Placebo Lead-In/ Drug Washout Weeks -6 -10 to -7 IMT assessment N = 720 Kastelien J. N Engl J Med. 2008; 358: 1431- 43. Ezetimibe 10 mg-Simvastatin 80 mg Simvastatin 80 mg Simvastatin 80 mg Ezetimibe 10 mg-Simvastatin 80 mg
ENHANCE Primary Outcome : Mean cIMT Kastelien J. N Engl J Med . 2008; 358: 1431- 43. 0.29 0.0111 ±0.0038 0.0058 ±0.0037 Change from baseline (mm) 0.29 0.71 ±0.15 0.70 ±0.14 Mean cIMT, 24 mo 0.64 0.69 ±0.13 0.70 ±0.13 Mean cIMT, baseline P value Simvastatin plus ezetimibe (n=338) Simvastatin monotherapy (n=342) Mean intima-media thickness of carotid artery (mm)
ENHANCE Mean cIMT during 24 months of therapy Mean cIMT (mm) Longitudinal, repeated measures analysis Kastelien J. N Engl J Med . 2008; 358: 1431- 43. 6 12 18 24 0.60 0.70 0.75 0.80 0.65 Months P=0.88 Simvastatin Eze-Simva
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