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Dr. Kees Hovingh, MD Academic Medical Centre, Amsterdam , The Netherlands

Master Class Lipid Innovations Prague, Czech Republic May 27-28, 2011. Presentation topic. The importance of lipid lowering through liver and intestine: An overview of all relevant data for atherosclerosis. Slide lecture prepared and held by:. Dr. Kees Hovingh, MD

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Dr. Kees Hovingh, MD Academic Medical Centre, Amsterdam , The Netherlands

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  1. MasterClassLipidInnovations Prague, Czech Republic May 27-28, 2011 Presentation topic The importance of lipid lowering through liver and intestine: An overview of all relevant data for atherosclerosis Slide lecture prepared and held by: Dr. Kees Hovingh, MD Academic Medical Centre, Amsterdam , The Netherlands

  2. Cholesterol: target? Br Med J 1992;305:15

  3. LDL lowering Primary prevention POSCH-PL 4S-PL Secondary prevention 25 POSCH-Rx 20 CARE-PL 4S-Rx 15 LIPID-PL % Patients with CHD Event TNT-10A CARE-Rx WOSCOPS-PL 10 LIPID-Rx TNT-80A WOSCOPS-Rx HPS-Rx LRC-PL 5 ASCOT-PL LRC-Rx ASCOT-Rx AFCAPS-PL AFCAPS-Rx 0 50 70 90 110 130 150 170 190 210 (mg/dL) 1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L) LDL cholesterol

  4. Statins : Corner Stone • CHD - stable • Low vs High TNT, IDEAL, SEARCH • Normal cholesterol ALLIANCE • Real World GREACE • Heart Failure CORONA / GISSI-HF • CHD – ACS • Low vs High dose PROVE-IT; A-Z • pre PTCA ARMYDA- Recapture NAPLES II • STROKE • Normal cholesterol SPARCL • No CHD • High CRP JUPITER • Asian population J-LIT, MEGA • IMAGING • FH ASAP/ ENHANCE • no CHD METEOR • Stable CHD REVERSAL, ASTEROID, SANDS • Children LIPIDS • CHD - stable • High cholesterol 4S • Normal cholesterol CARE/LIPID • CHD – ACS • Normal cholesterol MIRACL • PTCA AVERT • CHD - CABG • Normal cholesterol Post CABG • No CHD • High cholesterol WOSCOPS • Normal cholesterol AFCAPS/TEXCAPS • No CHD + risk factor • Hypertension ASCOT/ ALLHAT • Diabetes CARDS • SPECIAL GROUPS • high risk, low chol HPS • Elderly PROSPER • Renal Disease 4D, AURORA • Asian population J-LIT, MEGA

  5. CARDS5* ASCOT-LLA4 WOSCOPS2 4S3 HPS1 0 Reduction in major coronary events vs placebo (%) -27 -31 -34 -20 -36 -37 -40 Percent change Potential for further risk reduction -60 -80 -100 Statins: Effect on CAD Risk • 1. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22 • 2. Shepherd J et al. N Engl J Med. 1995;333:1301-1307 • 3. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389 • 4. Sever PS et al. Lancet. 2003;361:1149-1158 • 5. Colhoun HM et al. Lancet. 2004;364:685-696.

  6. Statin: “Rule of 6” 6% drop 6% drop Reduction of LDL-C, % 6% drop Guideline 0 10 20 30 40 50 60 70 80 Statin, mg However...... In addition: compliance, adverse effects, misconception (no control of efficacy) Knopp RH. N Engl J Med. 1999;341:498–511; Stein EA. Am J Cardiol. 2002;89(suppl):50C–57C.

  7. 5 Liver 5 4 2 7 10 Peripheral cells Cholesterol balance (µmol/day.100 g body wt) in mice VLDL LDL Forward pathway LDL Reverse pathway HDL Bile Feces Diet Duodenum Jejunum Ileum

  8. Ezetimibe Ezetimibe Ezetimibe Ezetimibe Ezetimibe Control Control Control Control Control Ezetimibe strongly increases TICE bile TICE (re)absorption Feces Diet Courtesy Prof Groen, UMCG

  9. Liver 300 Peripheral cells Cholesterol fluxes (mg/day.70 kg body wt) in man VLDL LDL Forward pathway LDL Reverse pathway HDL Bile 700 1000 700 Feces Diet 1000 400 Duodenum Jejunum Ileum

  10. StatinEffect on Cholesterol Absorption and Production Statin 10–80 mg (n=232) Placebo (n=62) 30 21 20 10 3 0.4 0 Mean change in ratio*at 12 weeks –4 –10 –20 –30 –27 –40 –38 –50 Total cholesterol Cholesterol production Cholesterol absorption *Ratio (sterol:TC)=mean (102 mmol/mol). Sterol=sitosterol (absorption) and lathosterol (production) Adapted from Assman G et al. Poster presented at the American College of Cardiology, New Orleans, Louisiana, USA, March 7–10, 2004.

  11. EzetimibeEffect on Cholesterol Absorption and Production Cholesterol Production % change Cholesterol Absorption +89% p < 0.001 p < 0.001 -54% Sudhop T et al. Circulation. 2002;106:1943-1948

  12. Ezetimibe/SimvastatinDual Action Peripheral Tissues Cholesterol 2/3 Bile Liver Absorption Production 1/3Food Inhibition ofcholesterolabsorption and production Small Intestine Lower LDL-C Blood Vessel Adapted from van Heek M, et al. Br J Pharmacol. 2000;129:1748–1754; Shepherd J. Eur Heart J Suppl. 2001;3(suppl E):E2–E5; Bays H. Expert OpinInvestig Drugs. 2002;11:1587–1604.

  13. Ezetimibe + Statin=Reduced Cholesterol Absorption and Production Placebo (n=62) Statin 10–80 mg (n=232) Ezetimibe 10 mg + statin 10–80 mg (n=229) 30 21 20 3 10 Mean change at 12 weeks 0.4 0 –4 –10 –20 –22 –30 –25 –27 –40 –38 –38 –50 Total cholesterol Cholesterol production Cholesterol absorption Sitosterol (absorption) and lathosterol (production) Assmann G et al. Poster American College of Cardiology

  14. LDL-C–Lowering Study 1 Study 2 0 0 –1% –5 –5 –4% –10 –10 –15 –15 Mean Change From Baseline,a % Mean Change From Baseline,a % –20 –20 –25 –25 –25% –27% –30 –30 Ezetimibe + simvastatin 10–20 mg (n=204) Placebo + simvastatin 10–20 mg (n=207) Ezetimibe + simvastatin 10–20 mg (n=179) Placebo + simvastatin 10–20 mg (n=186) Brohet C, et al. Curr Med Res Opin. 2005;21(4):571–578; Farnier M, Volpe M, Massaad R, et al. Int J Cardiol. 2005;102:327–332.

  15. Ezetimibe + SimvastatinSuperior Goal Attainment Study 1 Study 2 100 100 80% 74% 80 80 60 60 Patients at LDL-C Goal % Patients at LDL-C Goal % 40 40 17% 17% 20 20 0 0 Ezetimibe + simvastatin 10–20 mg (n=204) Placebo + simvastatin 10–20 mg (n=207) Ezetimibe + simvastatin 10–20 mg (n=179) Placebo + simvastatin 10–20 mg (n=186) Brohet C,. Curr Med Res Opin. 2005;21(4):571–578; Farnier M, Volpe M, Massaad R, et al. Int J Cardiol. 2005;102:327–332.

  16. Different statin, ... similar result 0 –5 –4% –10 –15 LS Mean % Change From Baselinea to Week 6 –20 –25 –30 –31%b –35 Ezetimibe 10 mg + atorvastatin 10 mg to 20 mg (n=219) Placebo + atorvastatin 10 mg to 20 mg (n=225) Adapted from Cruz-Fernández JM, et al. Int J ClinPract. 2005;59:619–627.

  17. Effects of Rosuvastatin + Ezetimibe Ezetimibe 10 mg + rosuvastatin 40 mg Rosuvastatin 40 mg P=NS 20 11 9 0 –20 25 Change From Baseline, % 35 –40 42 P<0.001 51 52 –60 57 P<0.001 65 70 –80 P<0.001 P<0.001 LDL-C TotalCholesterol HDL-C Non–HDL-C Triglycerides CM Ballantyne. Am J Cardiol 2007;99:673– 680

  18. Laboratory Values: Muscle and Liver

  19. ENHANCE

  20. ENHANCE IMT No change LDL lowering Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43

  21. P <0.05 SimvaLDLc -40% SimvaLDLc -40% Simva/EzeLDLc -57% AtorvaLDLc -52% ASAP vs ENHANCE ASAP 0.95 progression 0.90 0.85 cIMT mm 0.80 ENHANCE 0.75 0.70 0.65 regression 0 2 1 years

  22. Conclusions • Statins: first step • Need for additional therapy • Cholesterol absorption inhibition + Statin = two hits on cholesterol metabolism • CVD outcome: • SEAS (post-hoc, sec endpoint), SHARP (no Ezetimibe-only arm); IMPROVE-IT: answer

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