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 pool+foam cells+ TF expression Low chol. diet High chol. diet 16 months • 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.

3. Response-to-retention LDL Cell Adhesion Molecule Endothelium Basement Memb. NEFA Lysophospholipid Ceramides Oxidation prod Retained, Modified. LDL Hemin H2O2 Myeloperoxidase npsPLA2 Sphingomyelinase 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 Adipose tissue FFA TG Liver FFA HL TG HDL3 HDL2 CETP CE HL CE VLDL CETP TG LDL LDL

7. Plasma FFA Stimulation of CETP activity. TG formation by the liver TG rich VLDL. Insulin Resistance syndrome. [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 MI+CHD death +Stroke 24% P<0.001

10. 3,5 3 85 55 25 2,5 2 Relative Risk 1,5 1 0,5 0 100 160 220 LDL mg/dL Framingham Study:Relative 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. Age. Gender. Systolic BP. Smoking. Total cholesterol. Family history. LDL. HDL. Trigs. Obesity. Framingham risk score

14. 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 Normal CRP ---- no benefit CRP > 1.6mg/L 5.7%---- 3.9% CRP < 1.6mg/L 5.2%----- 2.1% hs-CRP>1.6 5.2%----3.1%

15. The metabolic syndrome: Any 3 of the following: • TG > 150. • HDL <40(m),< 50(f). • BP >130/>85. • FBG>110. • 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% (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.

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 1999;282:2340-2346

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 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.

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 <100 100 >100 to 130 risk equivalent† 2+ risk factors <130 130 >130 to 160 0-1 risk factor <160 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.

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 Total Population TG >300mg/l 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. 0% -10% -10% -13% -15% -15% -17% -20% -19% -20% -30% -31% -32% -40% Statins Efficacy on TG LESCOL XL Simvastatin Pravastatin Atorvastatin Total 20mg 40mg 20mg 40mg 10mg 20mg 40mg TG > 300 mg/dl 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® 40 mg qpm(n=543) Lescol® 40 mg bid(n=368) Lescol® XL 80 mg(n=912) ALT or AST Creatine kinase (CK) 1.9% 0% 1.7% 0.4% 4.3% 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

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 (n=13) (n=3) (n=12) (n=8) (n=8) (n=2) (n=16) 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 P<0.001 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 HDL2 Macrophage 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 2000;108:496-99. -23% < 2RFs&no CAD(low risk) -47% 2or more RFs&no 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. LCAS1 LCAS2 LISA3 FLARE4 (n= 365) (n= 834) (n= 429) Low HDL (n= 68) Per cent reduction in cardiovascular events Powerful Reductions In CardiovascularEvents With Lescol In CHD Patients 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.

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. 65 Ys F. Not overwt. Type 2 DM. Hypertrigs, 3 months Fenofibrate. Controled diet Metformin 1000mg BID. Ho AF,on warfarin. BP 128/85. Lipid case: Management of combined hyperlipidemia in a 65 year old female.

44. FBG: 170mg/dl (300 before metformin). HbA1c: 8.5%. TC: 284mg/dl. HDLc: 29mg/dl TG: 432mg/dl. Laboratory findings:

45. Does she have the metabolic syndrome? • 1. Yes • 2. No

46. The metabolic syndrome: Any 3 of the following: • TG > 150. • HDL <40(m),< 50(f). • BP >130/>85. • FBG>110. • Abdominal obesity.

47. 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.

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) (TC=LDLc+HDLc+TG/5). • By Direct measurement.

50. 1.Optimize glycemic control. 2.Achieve LDL target. 3.Achieve TG target. 4.Achieve HDLc target. 5.Achieve BP control. Which of the following is the most important initial goal for this pt.: