Management of dyslipidemia Pathogenestic consideration.

1
Management of dyslipidemia Pathogenestic
consideration.
By Ashraf Reda
,MD Prof. and head of cardiology Dep.
Menoufyia university.
2
The lipid theory
Balloon injury Atherogenic diet(rabbits)
SMC
Fibrous cap
Lipid poolfoam cells TF expression
Low chol. diet
High chol. diet
16 months

• inflammatory cells
• MMP-1
• interstitial collagen
• intima TF
• CD 154CD 40

-MMP-1 -Filamentous, scant collagen -TF
expression -CD 154 CD40
Aikawa et al, 1998,1999.
3
Response-to-retention
LDL
Cell Adhesion Molecule
Endothelium
Basement Memb.
NEFA Lysophospholipid Ceramides Oxidation prod
Retained, Modified.
LDL
Hemin H2O2 Myeloperoxidase npsPLA2 Sphingomyelinas
e
Macrophage
SMC
Cytokines GFs
4
Small LDL high apoB
Quebec cardiovascular study
LDL
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


5
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 .

6
Effect of plasma FFA
FFA TG
Adipose tissue
Liver
FFA
HL
TG
HDL3
HDL2
CETP
CE
HL
CE
VLDL
CETP
LDL
TG
LDL
7
Insulin Resistance syndrome.

• Plasma FFA
• Stimulation of CETP activity.

• TG formation by the liver
• TG rich VLDL.

impaired peripheral uptake
8

• Atherosclerosis with normal lipid parameters.
• Hyperlipidemia with no CAD.
• The issue of trigs.,and HDL.
• Proper risk assessment.

9
VA-HIT TRIAL
Gemfibrozil 1200mg
TG 31
No LDL change
HDL 6
Risk reduction
MICHD death Stroke
24
Plt0.001
10
Framingham StudyRelative Risk for CHD
Impact of High LDL and Low HDL
Kannel WB AJC 1983 52 9B -12B
11
Pathogenesis
Dyslipidemia
Risk factors
Modified LDL
Endothelial Dysfunction
Foam Cells
NO Endothelin Ang.-II Adhesion
molec. PAI-1
GFS Cytokines Metalloproteinasis Tissue factor
Atherosclerosis
12
How to risk stratify?
13
Framingham risk score

• Age.
• Gender.
• Systolic BP.
• Smoking.
• Total cholesterol.

• Family history.
• LDL.
• HDL.
• Trigs.
• Obesity.

14
CRP the tie-breaker in Primary prevention
AFCAPS/TexCAPS
N6605(LDL130-190) 5.2 Yrs treatment TargetLDL lt
110 Lovastatin vs placebo
Cost effective strategy at LDL gt150
LDL lt 150
Normal CRP ---- no benefit
CRP gt 1.6mg/L 5.7---- 3.9
CRP lt 1.6mg/L 5.2----- 2.1
hs-CRPgt1.6 5.2----3.1
15
The metabolic syndrome Any 3 of the following

• TG gt 150.
• HDL lt40(m),lt 50(f).
• BP gt130/gt85.
• FBGgt110.
• Abdominal obesity.

16
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 (Plt0.001)
• total mortality decreased by 11 (Plt0.001)
• Decreases were similar for all treatment
  modalities
• Cholesterol reduction did not increase non-CHD
  mortality

Gould AL et al. Circulation. 199897946-952.
17
Statins Clinical Trials reduction in LDL-C Vs
Coronary events
Reduction in coronary Events
Modifications in LDL-C
Trial
4S (simvastatin) -36 -38 CARE
(pravastatin) -28 -25 WOSCOPS
(pravastatin) -26 -31 LIPID (pravastatin)
-25 -25 AFCAPS/TexCAPS (Lovastatin)
-27 -38 FLARE (Fluvastatin) -38 -63
La Rosa et al. JAMA 19992822340-2346
18
Powerful Reductions In CardiovascularEvents With
Lescol In CHD Patients
LCAS2
LISA3
FLARE4
LCAS1
(n 365)
(n 834)
(n 429)
Low HDL (n 68)
0
-25
-20
Per cent reduction in cardiovascular events
-40
-63
-60
-71
-75
-80
Herd et al, J Card 199780.278-286 Ballantyne,
Circulation 1999 99 736-743 Riegger et al 1999
144253-270 Serruys et al. Eur Heart J
19992058-69.
19
NCEP ATP III LDL Cholesterol Goalsand Therapy
Recommendations
LDL cholesterol level (mg/dL)
Initiate therapeutic lifestyle changes
Initiate drug therapy
Goal
CHD or CHD lt100 ?100 gt100 to ?130 risk
equivalent 2 risk factors lt130 ?130 gt130 to
?160 0-1 risk factor lt160 ?160 gt160 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.
20012852486-2497.
20
Statins efficacy on LDL-C
Simvastatin 20mg 40mg
Pravastatin 20mg 40mg
Atorvastatin 10mg 20mg 40mg
LESCOL XL
Jones et al, Am J Cardiol 1998 81 582-7
(Etude CURVES) Ballantyne et al, Clin Ther 2001
23(2) 177-192
21
Statins Efficacy on HDL-C
Simvastatin 20mg 40mg
Pravastatin 20mg 40mg
Atorvastatin 10mg 20mg 40mg
TG gt300mg/l
Total Population
LESCOL XL
Jones et al, Am J Cardiol 1998 81 582-7
(CURVES study) Ballantyne et al, Clin Ther 2001
23(2) 177-192
22
Statins Efficacy on TG
LESCOL XL
Simvastatin
Pravastatin
Atorvastatin
Total
20mg
40mg
TG gt 300 mg/dl
20mg
40mg
10mg 20mg 40mg
Patients
Jones et al, Am J Cardiol 1998 81 582-7
(Etude CURVES) Ballantyne et al, Clin Ther 2001
23(2) 177-192
23
Excellent Safety Profile With Fluvastatin XL
Lescol
Cerivastatina
Pravastatin
Simvastatinb
Atorvastatinc


Warfarin
-





Digoxin





Niacin

No data



Erythromycin





Cyclosporin



Fibrates




Corsini et al, 1999, Pharmacol Therapeutics
1999 Vol 84 413-428 with additional information
from aRodriguez et al, 2000 Muck, 1998
Bermingham et al, 2000 Pogson et al, 1999
bGruer et al, 1999 cMaltz et al, 1999
Atorvastatin product monograph, Siedelik et al,
1999. Fischer et al Drug Metabolsim
Pharmacokinetics 1999 27 No 3 410-416
24
Interaction with Plavix

• Lipophilic statin reduce the platelet inhibitory
  effect of clopidogril

25
Fluvastatin XL low incidence of notable
laboratory test abnormalities
Lescol XL 80 mg(n912)
Lescol 40 mg qpm(n543)
Lescol 40 mg bid(n368)
ALT or AST Creatine kinase (CK)
1.9 0
1.7 0.4
4.3 0
notable gt3 x upper limit of normal (ULN) on two
consecutive occasions for AST and ALT and ? 10 x
ULN on one occasion for CK
26
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.

27
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

28
Thank you
29
What have we learned from lipid lowering trials
Bucher et al. Arterioscl Thromb Vasc Biol 1999
Harm
Benefit
Statin n-3FA Fibrates Resins Horm.
Niacin Diet (n13) (n3) (n12)
(n8) (n8) (n2) (n16)
Treated 85,431. Control 87,729 .
30
Benefits of statin therapy Mechanisms?

• LDL lowering.
• Pleotropic effects ?????.

31
Unanswered Questions In Atherosclerosis
Why do patients die with MI despite
hypolipidemic therapy?
32
The CARE study
Plt0.001
NS
Results according to TG at entry
33
Lipoprotein remodeling

STEROIDS
LDL Rec
LPL
BILEACIDS CELLMEMB.
HL
SRB1
VLDL
IDL
Other Receptors
LDL
OX LDL
EXESS
CETP
SRA
FC
Macrophage
HDL2
HL
LCAT
CETP
LCAT
HDL3
34
Hypertriglyceridemia
CETP
LDL
X
IDL
VLDL
Liver
C E T P
CETP
X
B.V
HDL
35
Is there another possiblepathology?
36
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?
37
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
38
Lipid Treatment Assessment Project (L-TAP)
Siegel et al, AM J Med 2000108496-99.
-23 lt 2RFsno CAD(low risk) -47 2or more RFsno
CAD(high risk) -30 established CAD
4888 participants
Overall achievement of LDL goals 38
Success rate()
39
Proven Mortality Benefit
A 28 Reduction in LDL-C significantly reduces
cardiovascular events
Major coronary events
Coronary deaths
Cardiovascular deaths
All-cause deaths

• 0

• -5

• -10

• -15

Per cent proportional risk reduction

• -21

• -20

• -27

• -25

• -29

• -31

• -30

• -35

Meta-analysis illustrating the beneficial effects
of statin therapy
LaRosa et al, JAMA 1999 282 2340-2346
40
Powerful Reductions In CardiovascularEvents With
Lescol In CHD Patients
Herd et al, J Card 199780.278-286 Ballantyne,
Circulation 1999 99 736-743 Riegger et al 1999
144253-270 Serruys et al. Eur Heart J
19992058-69.
41
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?
42
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?
43
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.

44
Laboratory findings

• FBG 170mg/dl (300 before metformin).
• HbA1c 8.5.

• TC 284mg/dl.
• HDLc 29mg/dl
• TG 432mg/dl.

45
Does she have the metabolic syndrome?

• 1. Yes
• 2. No

46
The metabolic syndrome Any 3 of the following

• TG gt 150.
• HDL lt40(m),lt 50(f).
• BP gt130/gt85.
• FBGgt110.
• Abdominal obesity.

47
What lipid target would you recommend?

• 1. LDLc lt 100 mg/dl.
• 2. LDLclt 100 and HDLcgt 40mg/dl.
• 3. LDLclt 100, HDLgt 40 and TGlt 200.
• 4. LDLclt130,HDLcgt40 and TGlt150.

48
ATPIII CHD risk equivalents

• Other clinical forms of atherosclerosis.
  PVD----Abd Ao An----Carotid artery D.
• DM.
• Multiple RFs.

49
How would you determine her LDLc level

• 1. By calculation (standered estimate)
  (TCLDLcHDLcTG/5).
• By Direct measurement.

50
Which of the following is the most important
initial goal for this pt.

• 1.Optimize glycemic control.
• 2.Achieve LDL target.
• 3.Achieve TG target.

• 4.Achieve HDLc target.
• 5.Achieve BP control.

51
To optimize her glycemic control, what would you
recommend?

• 1. Dose of metform.
• 2.Add SU.
• 3.Replace Metf.with SU.
• 4.Add PPAR-agonist.

• 5.Replace metf.with PPAR-agonist.
• 6.Add insulin.
• 7.Replace with insuline.

52
To optimize her lipid profile

• 1.Optimize now.
• 2.Reasses after2Ws of glycemic control.

• 3.Reasses after 6 Ws of glycemic control.
• 4.Reasses after 6 months.

53
6 weeks later

• FBG 99mg/dl.
• HbA1c 6.8.
• TC 236(from284).

• LDLc 140(from150).
• HDLc 32(from29).
• TG 320(from 432).

54
What would be your next step

• 1. Low dose statin.
• 2. Low dose statin and DC fenofib.
• 3. High dose statin.
• 4. 3 And DC fenofib.

• 5. Maximize fenofib.
• 6. Start LA niacin.
• 7. Start bile acid seq.
• 8. Start fish oil supl.

55
6 months later with 10 mg statin

• Well controlled DM, diet and exercise.
• LDLc95mg/dl,but TG325mg/dl.
• Statin increased to 40 mg myositis.

56
Fenofibrate was increased (in addition to
low Dose statin) TC163 LDL95
HDL42 TG130
57
Thank you
58
Lipid case

• 45 asymptomatic male.
• Worried because his TC is high and his brother
  had a history of a heart attack .
• TC233mg/dl HDL37 TG180
• FBG 122
• BMI 29 Kg/m2
• HR 74/m BP 146/88

59
What additional history would you obtain?

• 1. Family history of cardiac disease.
• 2. Family history of DM.
• 3. History of DM.

• 4. History of hypertension.
• 5. History of smoking.
• 6. Physical activity level.

60
By standard (Friedwald) formula
LDL160mg/dl.Which type of LDLc measurement
would you check?

• 1. Standard estimate.
• ( TC LDL HDL TG/5).
• 2. Direct estimate.

61
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.

62
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 doesnt have Htn.
• 4. Order 24hs ambulatory BP.

63
JNC VI

• High normal BP 130-139/85-89.
• Stage I 140-159/90-99.
• Stage II-III gt 160/100.

64
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.
65
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.

66
Based on FH, several component of the metabolic
S,and sedentary life What is yourassessment of
CV risk?

• 1. Very low.
• 2. Low.
• 3. Moderate.
• 4. High.
• 5. Very high.

67
What would be your next step?

• 1. Life style modification.
• 2. Drug therapy.
• 3. Both of them.

68
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.

69
What LDLc target are you for in this Pt.

• 1. lt 80 mg/dl.
• 2. lt 100 mg/dl.
• 3. lt 130 mg/dl.
• 4. lt 160 mg/dl.

70
ATPIII LDLc goals

• 1. CAD CAD risk equivalent ( 10 Yrs risk gt 20)
  lt 100mg/dl.
• gt 2 RFs (risklt20) lt130mg/dl.
• 0-1 RFs lt160mg/dl.

71
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.

72
The Pt. Inquires about whether he should undergo
exercise treadmill testing?What would you
recommend?

• 1. Symptom-limited test.
• 2. No cardiac testing necessary.

73
Negative EST apart from up-sloping ST depression.
74
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.

75
2 years OK. He discontinued LSM.5 Years later he
developed anterior MI. Coronary angio done and
revealed 3 vessel disease. CABG was done.
76
Heart protection study Major Vascular Events
77
HDL,Lipoprotein Remodeling, and CETP .

• Ashraf Reda , M.D.

78
Lipoprotein Remodeling

• Plasma enzymesTransfer protein
• Atherogenic potential Cardio
  protective
• Receptor mediated uptake

79
Potential pathogenetic mechanisms
c.p
Chronic infection Chronic immune activation
Transfer within monocyte cycle
IL6-TNF
Monocyte
CRP Fibrinogen Neopterin Chemokines

Tissue factors
VCAM-1-ICAM-1
Thrombin
E.C
Endothelial damage
Foam cells
SMC