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Prof. Alberto Corsini University of Milan Italy

The importance of lipid lowering through liver and intestine: An overview of all relevant data for atherosclerosis. Prof. Alberto Corsini University of Milan Italy. Factors affecting the response to statins. Intrinsic factors (genetically-determined). LDL-receptor gene mutations

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Prof. Alberto Corsini University of Milan Italy

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

  3. Risk:Benefit Ratio of Statin Titration Atorvastatin Lovastatin Simvastatin 40 mg 80 mg 10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 0 -10 -20 % Decrease in LDL-C -30 -40 -50 -60 2.5 4 x 2.0 2.3 x Elevated Transaminases (% of Patients) 1.5 1.7 x 1.0 0.5 0.0 10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 40 mg 80 mg Data from prescribing information for atorvastatin, lovastatin, simvastatin. This does not represent data from a comparative study.

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

  10. Ashigh as 60% LDL-C lowering via dual inhibition Inhibition of absorption Inhibition of synthesis Dual inhibition Statin + EZETIMIBE absorption synthesis absorption synthesis CHANGE OF SYNTHESIS AND ABSORPTION MARKERS1 absorption synthesis LDL-C LDL-C LDL-C 10% 20% STATIN + 20% 30% MEAN LDL-C LOWERING2,3 30-45% 40% EZETIMIBE 50% As high as 60% 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 etal. J Am Coll Cardiol 2002; 40:2125-34.

  11. Consistency of Co-Administration Studies Ezetimibe lowers LDL-C an added 19%-23% compared with statin alone Lova Prava Simva Atorva Add-On Co-admin Co-admin Co-admin Co-admin Study 0 20 Statin alone Statin + EZE 40 60 LDL-C (mg/dL) at study end 80 23% 23% 100 21% 19% 21% 120 140 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.

  12. Eze + RosuvavsRosuvaUptitration (the ACTE Study) (n=99) (n=98) (n=122) (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 Study Design - 6 - 5 - 1 0 6 Week Rosuva 5 mg + Eze 10 mg Rosuvastatin 10 mg Randomization Rosuvastatin 5 mg Run-in Screening Stratum II Rosuva 10 mg + Eze 10 mg Rosuvastatin 10 mg Rosuvastatin 20 mg Stratum I LDL-C not at goal * Bays et al. Am J Cardiol 2011; 108: 523-30

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

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

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

  16. Ezetimibealone and in combinationlowers the concentration of small, dense low-densitylipoproteins in type 2 diabetesmellitus 6-weektreatmenteffect of Eze 10 mg, Simva 20 mg and Combinationon concentrations of sd LDL (41 patients) % 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

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

  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. Proposedmechanisms for NPC1L1 deficiency or ezetimibetreatment to prevent NAFLD Ezetimibe Jia et al. AnnuRevPhysiol 2011; 73: 239-59

  21. Effects of low-dose simvastatin and ezetimibecomparedto high-dose simvastatin on endothelialfunction 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 Sameincreases 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. EurHeart J 2008; 29: 1753-60

  22. NS p = 0.001 Low dose Simvastatin and Eze preserved post-fat load endothelial function in male MS patients 10 8 6 % FMD (mg/dL) 4 Baseline values 2 After Oral Fat Load 0 Simva 80mg Simva 10 + Eze 10mg 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

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

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

  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

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