Transcript CETP-The Lipid Shuttle
Management of dyslipidemia Pathogenestic consideration. By Ashraf Reda ,MD Prof. and head of cardiology Dep.
Menoufyia university.
The lipid theory Balloon injury& Atherogenic diet(rabbits) Fibrous cap SMC+++ Lipid pool+foam cells+ TF expression Low chol. diet High chol. diet 16 months
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inflammatory cells MMP-1 interstitial collagen intima TF CD 154&CD 40 MMP-1 -Filamentous, scant collagen -TF expression -CD 154& CD40 Aikawa et al, 1998,1999.
Response-to-retention LDL Endothelium Cell Adhesion Molecule Basement Memb.
Retained, Modified.
LDL NEFA Lysophospholipid Ceramides Oxidation prod Hemin H 2 O 2 Myeloperoxidase nps PLA 2 Sphingomyelinase SMC Macrophage Cytokines GFs
LDL Small LDL & high apoB Quebec cardiovascular study apoB Risk(odds ratio) Large Low 1.0
Small high 6.2
N.B. 25.6nm for LDL size and 120mg/dl for apoB were the cut points
LIPS:
Lescole Intervention Prevention Study
LIPS is the first prospective trial to demonstrate the benefits of statin therapy (fluvastatin 80 mg/d) in patients post-first PCI (
stent) for reducing major adverse cardiac events
The risk of MACEs was significantly reduced by 22% over 4 years reaching 47 % with diabetics .
Effect of plasma FFA Adipose tissue FFA HL HDL3 LDL HL TG HDL2 CETP CE CE CETP TG LDL FFA TG Liver VLDL
Insulin Resistance syndrome.
Plasma FFA
[impaired peripheral uptake]
TG formation by the liver
Stimulation of CETP activity.
TG rich VLDL.
Atherosclerosis with normal lipid parameters.
Hyperlipidemia with no CAD.
The issue of trigs.,and HDL.
Proper risk assessment.
VA-HIT TRIAL Gemfibrozil 1200mg TG 31% No LDL change HDL 6% MI+CHD death +Stroke
Risk reduction
24% P<0.001
Framingham Study:
Relative Risk for CHD
Impact of High LDL and Low HDL 3,5 3 2,5 2 1,5 1 0,5 0 85 55 25 100 160 LDL mg/dL 220 Kannel WB AJC 1983: 52: 9B -12B
Pathogenesis NO Ang.-II PAI-1 Risk factors Endothelial Dysfunction Endothelin Adhesion molec.
Atherosclerosis Dyslipidemia Modified LDL Foam Cells GFS Cytokines Metalloproteinasis Tissue factor
How to risk stratify?
Framingham risk score
Age.
Gender.
Systolic BP.
Smoking.
Total cholesterol.
Family history.
LDL.
HDL.
Trigs.
Obesity.
CRP the ”tie-breaker” in Primary prevention AFCAPS/TexCAPS
N=6605(LDL130-190) 5.2 Yrs treatment Target:LDL < 110 Lovastatin vs placebo
Cost effective strategy at LDL >150 LDL < 150 CRP > 1.6mg/L 5.7%---- 3.9% CRP < 1.6mg/L 5.2%----- 2.1% Normal CRP ---- no benefit hs-CRP>1.6 5.2%----3.1%
The metabolic syndrome: Any 3 of the following:
TG > 150.
HDL <40(m),< 50(f).
BP >130/>85.
FBG>110.
Abdominal obesity.
Clinical Benefits of Cholesterol Reduction
A recent meta-analysis of 38 trials demonstrated that for every 10% reduction in TC – – CHD mortality decreased by 15% ( P <0.001) total mortality decreased by 11% ( P <0.001) Decreases were similar for all treatment modalities Cholesterol reduction did not increase non CHD mortality
Gould AL et al. Circulation. 1998;97:946-952.
Statins Clinical Trials : reduction in LDL-C Vs Coronary events Trial Modifications in LDL-C Reduction in coronary Events 4S (simvastatin) CARE (pravastatin) WOSCOPS (pravastatin) LIPID (pravastatin) AFCAPS/TexCAPS (Lovastatin*) FLARE (Fluvastatin) -36% -28% -26% -25% -27% -38% -38% -25% -31% -25% -38% -63%
La Rosa et al. JAMA 1999;282:2340-2346
Powerful Reductions In Cardiovascular Events With Lescol ® In CHD Patients 0 LCAS 1
(n= 429)
LCAS 2
Low HDL (n= 68)
LISA 3
(n= 365)
FLARE 4
(n= 834)
-20 -25 % -40 -60 -75 % -80
Herd et al, J Card 1997;80.278-286 Ballantyne, Circulation 1999; 99: 736 743 Riegger et al 1999; 144:253-270 Serruys et al. Eur Heart J 1999;20:58 69.
-71 % -63 %
NCEP ATP III LDL Cholesterol Goals and Therapy Recommendations
CHD or CHD risk equivalent † 2+ risk factors 0-1 risk factor Goal LDL cholesterol level (mg/dL) Initiate therapeutic lifestyle changes Initiate drug therapy* <100 <130 <160 100 130 160 >100 to 130 >130 to 160 >160 to 190 *Authorities disagree on when to initiate drug therapy.
† This category refers to patients without clinically evident CHD, but who have a similar risk for CHD events (eg, patients with diabetes, multiple risk factors, or other forms of atherosclerotic disease, such as peripheral artery disease).
NCEP ATP III guidelines.
JAMA.
2001;285:2486-2497.
Statins efficacy on LDL-C 0 Simvastatin 20mg 40mg Pravastatin 20mg 40mg Atorvastatin 10mg 20mg 40mg LESCOL XL -10 -20 -24 -30 -40 -35 -41 -50 -34 -60
Jones et al, Am J Cardiol 1998 ; 81 : 582-7 (Etude CURVES) Ballantyne et al, Clin Ther 2001 ; 23(2) : 177-192
-38 -46 -51 -41
Statins Efficacy on HDL-C 21% 18% 15% 12% 9,6% 9% 6% 5,2% 3% 6,2% 3,0% 5,5% 5,1% 4,8% 9% 21% 0% Simvastatin 20mg 40mg Pravastatin 20mg 40mg
Jones et al, Am J Cardiol 1998 ; 81 : 582-7 (CURVES study) Ballantyne et al, Clin Ther 2001 ; 23(2) : 177-192
Atorvastatin Total Population 10mg 20mg 40mg TG >300mg/l LESCOL XL
Statins Efficacy on TG 0% Simvastatin 20mg 40mg Pravastatin 20mg 40mg Atorvastatin 10mg 20mg 40mg LESCOL XL Total Patients TG > 300 mg/dl -10%
-10% -15% -13%
-20% -30% -40%
Jones et al, Am J Cardiol 1998 ; 81 : 582-7 (Etude CURVES) Ballantyne et al, Clin Ther 2001 ; 23(2) : 177-192
-20% -32% -19% -31%
Excellent Safety Profile With Fluvastatin XL Warfarin Digoxin Niacin Erythromycin Lescol ® Cerivastatin a Pravastatin Simvastatin b Atorvastatin c – – + – – – – – No data – – – – + – + – – – Cyclosporin Fibrates – – + + + + + + + + Corsini et al, 1999, Pharmacol & Therapeutics 1999 Vol 84; 413-428 with additional information from a Rodriguez et al, 2000; Muck, 1998; Bermingham et al, 2000; Pogson et al, 1999; b Gruer et al, 1999; c Maltz et al, 1999; Atorvastatin product monograph, Siedelik et al, 1999.
Fischer et al Drug Metabolsim & Pharmacokinetics 1999; 27: No 3: 410-416
Interaction with Plavix
Lipophilic statin reduce the platelet inhibitory effect of clopidogril
Fluvastatin XL: low incidence of notable laboratory test abnormalities ALT or AST Creatine kinase (CK) Lescol ® XL 80 mg (n=912) Lescol ® 40 mg qpm (n=543) Lescol ® 40 mg bid (n=368) 1.9% 1.7% 4.3% 0% 0.4% 0% notable = >3 x upper limit of normal (ULN) on two consecutive occasions for AST and ALT and
10 x ULN on one occasion for CK
What the Ideal Statin Should be ?
The ideal Statin should:
Treat LDL, HDL and triglycerides comprehensively.
Attain treatment targets for all lipid parameters.
Exert safety profile.
Provide Cardiovascular benefits beyond LDL reduction.
Conclusions
Functional and structural lipoprotein profile deserve more attention.
The lipid theory is valid, but the interaction bet. Dyslipidemia and other risk factors could be the trigger.
Global risk evaluation is of utmost importance.
Safety is as important as efficacy on choice of the ideal statin
Thank you
What have we learned from lipid lowering trials: Bucher et al. Arterioscl Thromb Vasc Biol 1999 Harm 1.2
1 Benefit 0.8
0.6
0.4
0.2
0 Statin n-3FA Fibrates Resins Horm. Niacin Diet (n=13) (n=3) (n=12) (n=8) (n=8) (n=2) (n=16)
Treated: 85,431. Control: 87,729
. RR&95%CI
Benefits of statin therapy: Mechanisms?
LDL lowering.
Pleotropic effects
?????
.
Unanswered Questions In Atherosclerosis Why do patients die with MI despite hypolipidemic therapy?
The CARE study 35 30 25 20 15 10 5 0
P<0.001
<145
NS
>145 Results according to TG at entry %red.vs
placebo
LDL Rec Other Receptors SRB1
Lipoprotein remodeling
LPL HL STEROIDS BILEACIDS CELLMEMB.
VLDL CETP HL CETP HDL2 LCAT LCAT HDL3 LDL OX LDL EXESS SRA FC Macrophage
Hypertriglyceridemia
CETP VLDL CETP IDL C E T P LDL X Liver X B.V
HDL
Is there another possible pathology?
Unanswered Questions In Atherosclerosis Why are ischemic patients not always hyperlipidemic?
Why hyperlipedemic patients are not always ischemic?
Why do patients die with MI despite hypolipidemic therapy?
How can lipid lowering agents benefit normolipidemic subjects?
Effect of statin on lipoprotein remodeling Fluvastatin in post menopausal women 24% LDL reduction 42% reduction of small dense LDL 35% IDL reduction 22% ApoB reduction
Lipid Treatment Assessment Project (L-TAP):
Siegel et al, AM J Med 2000;108:496-99.
4888 participants -23% < 2RFs&no CAD(low risk) -47% 2or more RFs&no CAD(high risk) -30% established CAD Overall achievement of LDL goals 38% 70 60
Success rate(%)
50 40 30 20 10 0 CHD High risk Low risk
Proven Mortality Benefit A 28 % Reduction in LDL-C significantly reduces cardiovascular events Major coronary events Coronary deaths Cardiovascular deaths All-cause deaths
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0
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-5
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-10
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-15
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-20
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-25
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-30
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-31 %
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-29 %
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-27 %
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-21 %
•
-35 Meta-analysis illustrating the beneficial effects of statin therapy
LaRosa et al, JAMA 1999; 282: 2340-2346
Powerful Reductions In Cardiovascular Events With Lescol In CHD Patients LCAS 1 LCAS 2 LISA 3 FLARE 4
0
(n= 429) Low HDL (n= 68) (n= 365) (n= 834)
-20 -25 % -40 -60 -71 % -63 % -75 % -80
Herd et al, J Card 1997;80.278-286 Ballantyne, Circulation 1999; 99: 736-743 Riegger et al 1999; 144:253-270 Serruys et al. Eur Heart J 1999;20:58-69 .
Unanswered Questions In Atherosclerosis
Why ischemic patients are not always hyperlipidemic?
Why hyperlipedemic patients are not always ischemic?
Why do patients die with MI despite hypolipidemic therapy?
How can lipid lowering agents benefit normolipidemic subjects?
Unanswered Questions In Atherosclerosis Why ischemic patients are not always hyperlipidemic?
Why hyperlipedemic patients are not always ischemic?
Why do patients die with MI despite hypolipidemic therapy?
How can lipid lowering agents benefit normolipidemic subjects?
Lipid case: Management of combined hyperlipidemia in a 65 year old female.
65 Ys F.
Not overwt.
Type 2 DM.
Hypertrigs, 3 months Fenofibrate.
Controled diet Metformin 1000mg BID.
Ho AF,on warfarin.
BP 128/85.
Laboratory findings:
FBG: 170mg/dl (300 before metformin).
TC: 284mg/dl.
HDLc: 29mg/dl
HbA1c: 8.5%.
TG: 432mg/dl.
Does she have the metabolic syndrome?
1. Yes
2. No
The metabolic syndrome: Any 3 of the following:
TG > 150.
HDL <40(m),< 50(f).
BP >130/>85.
FBG>110.
Abdominal obesity.
What lipid target would you recommend?
1. LDLc < 100 mg/dl.
2. LDLc< 100 and HDLc> 40mg/dl.
3. LDLc< 100, HDL> 40 and TG< 200.
4. LDLc<130,HDLc>40 and TG<150.
ATPIII: CHD risk equivalents:
Other clinical forms of atherosclerosis. PVD----Abd Ao An----Carotid artery D.
DM.
Multiple RFs.
How would you determine her LDLc level:
1. By calculation (standered estimate) (TC=LDLc+HDLc+TG/5).
By Direct measurement.
Which of the following is the most important initial goal for this pt.:
1.Optimize glycemic control.
4.Achieve HDLc target.
2.Achieve LDL target.
5.Achieve BP control.
3.Achieve TG target.
To optimize her glycemic control, what would you recommend?
1. Dose of metform.
5.Replace metf.with PPAR -agonist.
2.Add SU.
6.Add insulin.
3.Replace Metf.with SU.
7.Replace with insuline.
4.Add PPAR-agonist.
To optimize her lipid profile:
1.Optimize now.
3.Reasses after 6 Ws of glycemic control.
2.Reasses after2Ws of glycemic control.
4.Reasses after 6 months.
6 weeks later:
FBG: 99mg/dl.
HbA1c: 6.8%.
TC: 236(from284).
LDLc: 140(from150).
HDLc: 32(from29).
TG: 320(from 432).
What would be your next step:
1. Low dose statin.
5. Maximize fenofib.
2. Low dose statin and DC fenofib.
6. Start LA niacin.
7. Start bile acid seq.
3. High dose statin.
4. 3 And DC fenofib.
8. Start fish oil supl.
6 months later with 10 mg statin:
Well controlled DM, diet and exercise.
LDLc:95mg/dl,but TG:325mg/dl.
Statin increased to 40 mg myositis.
Fenofibrate was increased (in addition to low Dose statin): TC:163 LDL:95 HDL:42 TG:130
Thank you
Lipid case:
45 asymptomatic male.
Worried because his TC is high and his brother had a history of a heart attack .
TC:233mg/dl HDL:37 TG:180
FBG: 122
BMI 29 Kg/m2
HR: 74/m BP: 146/88
What additional history would you obtain?
1. Family history of cardiac disease.
4. History of hypertension.
2. Family history of DM.
5. History of smoking.
3. History of DM.
6. Physical activity level.
By standard (Friedwald) formula: LDL=160mg/dl.
Which type of LDLc measurement would you check?
1. Standard estimate. ( TC= LDL+ HDL+ TG/5).
2. Direct estimate.
FBG = 122 mg/dl: What would be your next step?
1. Advise Pt, that he does not have DM.
Order HbA1c level.
Order glucose tolerance trst.
Regarding BP 146/88: what would you do?
1. Advise Pt. that he has hypertension.
2. Advise that he has mild hypertrnsion.
3. Advise that he probably doesn’t have Htn.
4. Order 24hs ambulatory BP.
JNC VI:
High normal BP: 130-139/85-89.
Stage I: 140-159/90-99.
Stage II-III: > 160/100.
To estimate his 10 year risk of coronary event: Which of the following factors are considered in the Framingham risk score.
1. Gender and Age.
3. TC.
5. Systolic BP.
7. FH.
9. Sedentary life.
11. TG.
2. LDLc.
4. HDLc.
6. Diastolic BP.
8. Smoking.
10. Obesity.
Choose one or more.
10-year CV risk according to Framingham---8%: Based on this formula, what is his level of risk?
1. Very low.
2. Low.
3. Moderate.
4. High.
5. Very high.
Based on: FH, several component of the metabolic S,and sedentary life: What is your assessment of CV risk?
1. Very low.
2. Low.
3. Moderate.
4. High.
5. Very high.
What would be your next step?
1. Life style modification.
2. Drug therapy.
3. Both of them.
What therapeutic LSM do you recommend?
1. AHA step I diet.
2. AHA step II diet.
3. Aerobic exercise 10-15min, 3-4 ds/w.
4. Aerobic exercise 20-30min, 3-5 ds/w.
5. Aerobic exercise 45-60min, 2-3 ds/w.
What LDLc target are you for in this Pt.
1. < 80 mg/dl.
2. < 100 mg/dl.
3. < 130 mg/dl.
4. < 160 mg/dl.
ATPIII LDLc goals:
1. CAD& CAD risk equivalent ( 10 Yrs risk > 20%): < 100mg/dl.
> 2 RFs (risk<20%): <130mg/dl.
0-1 RFs: <160mg/dl.
What would you recommend as first line therapy:
1. Start low dose statin.
2. Start a moderate dose statin.
3. High dose statin.
4. Long acting niacin.
5. Fibrate.
6. A bile acid sequestrant.
The Pt. Inquires about whether he should undergo exercise treadmill testing?
What would you recommend?
1. Symptom-limited test.
2. No cardiac testing necessary.
Negative EST apart from up-sloping ST depression.
He is still anxious about the the prospect of getting CAD. Given the FH, What would you do next?
1. Reassurance.
2. Exercise nuclear test.
3. Stress echo
4 Electron-beam CT.
5. Coronary angiography.
2 years OK. He discontinued LSM.
5 Years later he developed anterior MI. Coronary angio done and revealed 3 vessel disease. CABG was done.
Heart protection study: Major Vascular Events
Vascular event Total CHD Total stroke Revascularisation ANY OF ABOVE SIMVASTATIN (10269) PLACEBO (10267) Risk ratio and 95% CI STATIN better STATIN worse 914 456 926 2042 (19.9%) 1234 613 1185 2606 (25.4%) 0.4
0.6
0.8
1.0
1.2
24% SE 2.6
reduction (2P<0.00001) 1.4
HDL,Lipoprotein Remodeling, and CETP .
Ashraf Reda , M.D.
Lipoprotein Remodeling Plasma enzymes&Transfer protein
Atherogenic potential Cardio protective
Receptor mediated uptake
Potential pathogenetic mechanisms c.p
Transfer within monocyte cycle Monocyte Tissue factors IL6-TNF CRP Fibrinogen Neopterin Chemokines Chronic infection Chronic immune activation Thrombin Foam cells SMC