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

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

3. LDL lowering Primary prevention Secondary prevention 507011013015017019090210 % Patients with CHD Event LDL cholesterol CARE-Rx 4S-Rx LIPID-PL 4S-PL CARE-PL LIPID-Rx AFCAPS-Rx WOSCOPS-Rx WOSCOPS-PL AFCAPS-PL 25 20 15 10 5 0 ASCOT-PL ASCOT-Rx HPS-Rx LRC-PL LRC-Rx POSCH-PL POSCH-Rx (mg/dL) 1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L) TNT-80A TNT-10A

4. Statins : Corner Stone  CHD - stable  High cholesterol 4S  Normal cholesterolCARE/LIPID  CHD – ACS  Normal cholesterol MIRACL  PTCAAVERT  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  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

5. 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. Reduction in major coronary events vs placebo (%) Potential for further risk reduction WOSCOPS 2 -31 4S 3 -34 ASCOT- LLA 4 HPS 1 -27 CARDS 5 * -37 -40 -20 0 -60 -80 -100 Percent change -36

6. However...... 010305080 Statin, mg Reduction of LDL-C, % Statin: “Rule of 6” 20407060 6% drop Guideline Knopp RH. N Engl J Med. 1999;341:498–511; Stein EA. Am J Cardiol. 2002;89(suppl):50C–57C. In addition: compliance, adverse effects, misconception (no control of efficacy)

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

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

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

10. *Ratio (sterol:TC)=mean (10 2 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. Placebo (n=62) Statin 10–80 mg (n=232) 0.4 –27 3 –38 –4 21 –50 –40 –30 –20 –10 0 10 20 30 Mean change in ratio* at 12 weeks Total cholesterolCholesterol productionCholesterol absorption Statin Effect on Cholesterol Absorption and Production

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

12. Ezetimibe/Simvastatin Dual Action 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 Opin Investig Drugs. 2002;11:1587–1604. Peripheral Tissues Liver Cholesterol Production Absorption Inhibition of cholesterol absorption and productio n Blood Vessel Small Intestine 2/3 Bile 1/3 Food Lower LDL-C

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) Sitosterol (absorption) and lathosterol (production) Assmann G et al. Poster American College of Cardiology 0.4 –27 –38 3 –22 –4 21 –25 –50 –40 – 30 –20 – 10 0 10 20 30 Mean change at 12 weeks Total cholesterolCholesterol productionCholesterol absorption

14. 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. LDL-C–Lowering –30 –20 0 Mean Change From Baseline, a % –27% –5 –10 –15 –4% Mean Change From Baseline, a % 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) –25 –30 –20 0 –25% –5 –10 –15 –1% –25 Study 1Study 2

15. Ezetimibe + Simvastatin Superior Goal Attainment 0 20 100 Patients at LDL-C Goal % Ezetimibe + simvastatin 10–20 mg (n=204) Placebo + simvastatin 10–20 mg (n=207) 80% 80 60 40 17% 0 20 100 Patients at LDL-C Goal % Ezetimibe + simvastatin 10–20 mg (n=179) Placebo + simvastatin 10–20 mg (n=186) 74% 80 60 40 17% Study 1Study 2 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 Adapted from Cruz-Fernández JM, et al. Int J Clin Pract. 2005;59:619–627. –35 –30 –25 –20 –10 0 LS Mean % Change From Baseline a to Week 6 –31% b –4% –5 –15 Ezetimibe 10 mg + atorvastatin 10 mg to 20 mg (n=219) Placebo + atorvastatin 10 mg to 20 mg (n=225)

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

18. Laboratory Values: Muscle and Liver Eze/ Simva (n=1226) Ezetimibe (n=298) Simva 10 mg to 80 mg (n=1217) Placebo (n=307) CK > 10xULN0.20.00.30.7 ALT >3ULN1.60.00.70.3 AST >3xULN0.80.30.40.3

19. ENHANCE

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

21. ASAP vs ENHANCE regressio n progression cIMT mm years 0 1 2 0.8 0 0.8 5 0.7 5 0.9 0 0.9 5 0.7 0 0.6 5 ASAP Simva LDLc - 40% Atorva LDLc - 52% P <0.05 Simva LDLc -40% Simva/Eze LDLc - 57% ENHANCE

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