1. The importance of lipid lowering through liver and intestine: An overview of all relevant data for atherosclerosis Prof. Alberto Corsini University of Milan Italy

2. Factors affecting the response to statins poor compliance background diet dose and uptitration of drug concomitant drug therapy Extrinsic factors (extraneous influences) Intrinsic factors (genetically-determined) LDL-receptor gene mutations apo-B-100 gene mutations CYP/transporter polymorphism apoE polymorphism rate of cholesterol biosynthesis rate of cholesterol absorption

3. Data from prescribing information for atorvastatin, lovastatin, simvastatin. This does not represent data from a comparative study. Risk:Benefit Ratio of Statin Titration AtorvastatinLovastatin 20 mg40 mg80 mg 20 mg40 mg80 mg Simvastatin 40 mg80 mg 40 mg80 mg 1.7 x 2.3 x % Decrease in LDL-C 10 mg20 mg40 mg80 mg -60 -50 -40 -30 -20 -10 0 10 mg20 mg40 mg80 mg 0.0 0.5 1.0 1.5 2.0 2.5 Elevated Transaminases (% of Patients) 4 x

4. Muscular symptoms were reported in 10% of statin treated patients and led to discontinuation in 30% of the symptomatic patients Nutrition, Metabolism & Cardiovascular Diseases 1-5, 2012 in press

5. Preiss D et al

6. Individual responses of lipids and the plasma sterols among the statin treatment groups Van Himbergen TM et al. J Lip Res 54:730-9; 2009

7. Lathosterol and campesterol changes in relation to changes in total cholesterol and LDL cholesterol during statin treatment Van Himbergen TM et al. J Lip Res 54:730-9; 2009

8. Correlation of the synthesis and absorption markers with reductions in cholesterol and LDL-C Descamps OS et al. Atherosclerosis 217 (2011) 308 – 321

9. Dietary cholesterol Cholesterol DARM Excretion Dual Inhibition: Ezetimibe and Statin Synthesis of Cholesterol Bile Intestine Statin LDL-C absorption Ezetimibe

10. LDL-C 20% 30-45% STATIN + As high as 60% 10% 20% 30% 40% 50% MEAN LDL-C LOWERING 2,3 synthesis absorption synthesis absorption synthesis absorption As high as 60% LDL-C lowering via dual inhibition 1. Assmann G, et al. J Am Coll Cardiol 2004;43(5, Suppl. 2):A445-A446; 2. Goldberg AC, et al. Mayo Clin Proc. 2004 May;79(5):620-9.; 3. Davidson M et al. J Am Coll Cardiol 2002; 40:2125-34. CHANGE OF SYNTHESIS AND ABSORPTION MARKERS 1 Inhibition of absorption Dual inhibition Statin + EZETIMIBE Inhibition of synthesis EZETIMIBE

11. 0 20 40 60 80 100 120 140 Lova Co-admin Prava Co-admin Simva Co-admin Atorva Co-admin Add-On Study Statin alone Statin + EZE LDL-C (mg/dL) at study end Consistency of Co-Administration Studies 21% 19% 23% 21% Lipka L, et al. J Am Coll Cardiol (Suppl). 2002. Melani L, et al. J Am Coll Cardiol (Suppl). 2002. Davidson M, et al. J Am Coll Cardiol (Suppl). 2002. Ballantyne C, et al. J Am Coll Cardiol (Suppl). 2002. Bays H, et al. J Am Coll Cardiol (Suppl). 2002. Ezetimibe lowers LDL-C an added 19%-23% compared with statin alone

12. Eze + Rosuva vs Rosuva Uptitration (the ACTE Study) Study Design - 6 - 5 - 1 0 6 Week Rosuva 5 mg + Eze 10 mg Rosuvastatin 10 mg Randomization Rosuvastatin 5 mg (n=99) (n=122) LDL-C not at goal * Screening Run-in Rosuva 10 mg + Eze 10 mg Rosuvastatin 10 mg Rosuvastatin 20 mg (n=98) (n=121) * LDL-C target < 100 mg/dL for moderately high or high risk subjects without atherosclerotic vascular disease (AVD), < 70 mg/dl for high risk subjects with AVD Stratum I Stratum II Bays et al. Am J Cardiol 2011; 108: 523-30

13. Rosuva 5 mg and 10 mg + Ezetimibe vs Rosuva 10 mg and 20 mg (Pooled data) % change from baseline * * * * * p < 0.001 % change from baseline * * Bays et al. Am J Cardiol 2011; 108: 523-30

14. Attainement of pre-specified LDL-C targets after 6 weeks of therapy LDL-C < 100 mg/dL – Patients w/o AVD * * * * * p < 0.001 % patients attaining specified LDL-C target * * Across Strata Stratum I Stratum II LDL-C < 70 mg/dL – Patients w/ AVD n=219 n=217 n=98 n=96 n=121 n=121 Bays et al. Am J Cardiol 2011; 108: 523-30

15. Pooled-analysis of 27 clinical trials comparing the efficacy of Eze/Statin vs Statin therapies in patients with and without diabetes LDL-CNon-HDL-CApoB/ApoA1 with diabetes without diabetes with diabetes without diabetes with diabetes without diabetes % change from baseline Leiter et al. Diab Obes Metab 2011; 13: 615-28  -17.4%  -14.9%  -15.0%  -13.6%  -13.0%  -11.9% p < 0.0001 p = 0.0015 p = 0.0297  = difference vs statin alone n 3043 3394 7012 7831 3044 3397 7013 7832 2342 2467 4461 5238

16. Ezetimibe alone and in combination lowers the concentration of small, dense low-density lipoproteins in type 2 diabetes mellitus % Change p=0.043 p=0.029 p=0.02 p=0.007 p=0.003 p=0.002 p value versus baseline Winkler et al. Atherosclerosis 2012; 220: 189-93 6-week treatment effect of Eze 10 mg, Simva 20 mg and Combination on concentrations of sd LDL (41 patients)

17. Effect of Atorvastatin 20 mg and Atorvastatin/Ezetimibe 5/5 mg on Fasting and PP Triglycerides in Combined Hyperlipidemia Randomized, open-label study, 8 weeks of treatment; 60 patients with LDL-C > 130 mg/dL and TG 150-499 mg/dL * PP TG=post-prandial TG (2h after an oral fat load test) % change from baseline Lee et al. J Cardiol Pharmacol Ther 2012; 17: 65-71 p=0.07 p=0.03 p=0.12 p=0.04 p=0.09

18. The non alcoholic fatty liver disease (NAFLD) After an initial phase characterized by liver fat deposition, it may evolve to steatohepatitis, cyrrhosis and hepatocarcinoma, without abuse of alcohol. In the world the incidence is 25-30% in adults but it is rapidly growing also in children. Possible causes: obesity, metabolic syndrome, type II diabetes, nutritional imbalance, drug abuse and toxic exposure.

19. The sine qua non of fatty liver disease: hepatic triglyceride accumulation due to imbalance between TG acquisition and removal J C Cohen et al. Science 2011;332:1519-1523

20. Proposed mechanisms for NPC1L1 deficiency or ezetimibe treatment to prevent NAFLD Jia et al. Annu Rev Physiol 2011; 73: 239-59 Ezetimibe

21. Effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin on endothelial function  39 patients with type 2 diabetes or IGT and stable CAD  Randomized to Simva 80 mg or Eze/Simva 10/10 mg for 6 weeks Key results Same increases in FMD and decreases in CRP in both groups Conclusion Cholesterol lowering is more important than pleiotropic effects of statins for improvement in endothelial function and inflammatory markers. Settergren et al. Eur Heart J 2008; 29: 1753-60

22. After Oral Fat Load Baseline values Randomized double-blind crossover trial in 19 male obese patients with MS treated with high-dose simva 80 mg vs low-dose simva 10 mg + eze 10 mg Olijhoek JK et al. J Cardiovasc Pharmacol 2008; 52: 145-50 0 2 4 6 8 10 % FMD Simva 80mg Simva 10 + Eze 10mg NS p = 0.001 BaselineSimva 80 Simva 10 + EZ 10 LDL-C143±2781±19 TG143±26111±49127±49 HDL-C44±1044±1243±10 (mg/dL) Low dose Simvastatin and Eze preserved post-fat load endothelial function in male MS patients

23.  231 patients attending a Stroke Prevention Clinic (Ontario, Canada),(mainly patients unable to take high doses of statins) Effect of Ezetimibe on carotid plaque burden Bogiatzi et al. Stroke 2012; 43: 1153-5  Carotid total plaque area measured for 2 years before and 2 years after initiation of therapy.

24. Effect of Ezetimibe on carotid plaque burden Bogiatzi et al. Stroke 2012; 43: 1153-5 p < 0.01

25. Journal of Cardiology 158 (2012) 400–404 CAD patients (n=83, 63±9 years, 57% men) receiving S20, were randomly allocated to receive E10/S20 or S80, for 6 weeks Lipids, inflammatory markers (C-reactive protein, interleukin-6, monocyte chemoattractant protein-1, soluble CD40 ligand and oxidized LDL), and platelet aggregation (platelet function analyzer [PFA]-100) changes were determined

26. Percentual changes of LDL-C and inflammatory markers between randomized treatment groups Journal of Cardiology 158 (2012) 400–404

27. Take home messages  Optimal LDL-C lowering and therapeutical targets can be achieved by inhibiting cholesterol absorption and production with ezetimibe/simvastatin  The SHARP trial establish the clinical benefits of eze/simv consistently with meta-analysis of statin trials  Beyond its LDL-lowering effects, other potential benefits of ezetimibe have been recently described:  improvement of post-prandial hyperlipidemia  improvement of liver steatosis  positive effect on endothelial dysfunction  antiatherosclerotic benefits