1. The concept of Diabetes & CV risk: A lifetime risk challenge Vascular function as an early sign of trouble: How can the inhibition of cholesterol absorption reduce the atherogenic load of intestinal lipoproteins? Prof Frank Visseren, MD Academic Medical Centre Utrecht The Netherlands Master Class Lipid Innovations Prague, Czech Republic May 27-28, 2011 Slide lecture prepared and held by: Presentation topic

2. Overview of Cholesterol Transport

3. Altman SW et al. Science 2004;303:1201-1204 Cholesterol transporter

4. Postprandial lipidemia Postprandial lipids (triglyceride-rich lipoprotein or lipoprotein-remnant particles) are associated with: –Endothelial dysfunction –Elevated small LDL particles –Elevated Factor VII –Elevated plasminogen activator inhibitor-1 (PAI-1) –Elevated C-reactive protein (CRP)

5. Nordestgaard B, et al. JAMA 2007;298:299-308. Copenhagen City Heart Study

6. Nordestgaard B, et al. JAMA 2007;298:299-308. Triglyceride levels and levels of remnant lipoprotein cholesterol since last meal

7. Nordestgaard B, et al. JAMA 2007;298:299-308. Levels of Remnant Lipoprotein Cholesterol as a function of levels of nonfasting Triglycerides

8. Nordestgaard B, et al. JAMA 2007;298:299-308. Non-fasting triglycerides and risk for MI, IHD and death in Women

9. Nordestgaard B, et al. JAMA 2007;298:299-308. Non-fasting triglycerides and risk for MI, IHD and death in Men

10. Bansal S, et al. JAMA 2007;298:309-316. Women’s Health Study (WHS)

11. Bansal S, et al. JAMA 2007;298:309-316. Association of triglyceride levels with incident CVD according to fasting status

12. Bansal S, et al. JAMA 2007;298:309-316. Womens Health Study (WHS)

13. Triglyceride concentrations after an oral fatload in obese patients with metabolic syndrome Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150

14. Drop in HDL-c after an oral fatload Hajer et al. Clin Endocrinol 2008;69:870-877 N=19

15. Increase in Cholesterol Ester Transfer (CET) after an oral fatload Hajer et al. Clin Endocrinol 2008;69:870-877 N=19

16. Oral Triglyceride Tolerance Test!?? Standardized Oral Triglyceride Tolerance Test (OTTT): 1g dairy cream/kg body weight 50g fat plus 50 g carbohydrate Mixed meal But: No evidence for CVD risk stratification No evidence for clinical benefit of treatment of postprandial lipids

17. Effect of statin versus fibrate on postprandial endothelial dysfunction: role of remnant-like particles Wilmink H et al. Cardiovasc Res 2001;50:577-582 Randomized, placebo controlled trial Cerivastatin 0.4mg vs. gemfibrozil 900mg 15 healthy volunteers

18. Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction Yunoki K et al. Atherosclerosis 2011;epub N=19

19. Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction Yunoki K et al. Atherosclerosis 2011;epub N=19

20. washout Simva 80mg Simva/eze 10/10 washout Oral fatload 6 weeks4 weeks6 weeks FMD Simva/eze 10/10 Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150 Low-dose statin and ezetimibe compared to high-dose simvastatin on postprandial lipids in patients with the metabolic syndrome

21. Oral fatloading test Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150 Low-dose statin and ezetimibe compared to high-dose simvastatin on postprandial lipids in patients with the metabolic syndrome

22. p<0.001 Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150

23. Low-dose statin and ezetimibe compared to high-dose simvastatin on postprandial lipids in patients with the metabolic syndrome

24. Conclusions HDL-c drops after an oral fatload Statins, fibrates, statin/ezetimibe lower post-fatload hyperlipidemia (triglycerides, LDL-c, remnant particles) Statin monotherapy and Ezetimibe monotherapy preserve post-fatload endothelial function Combination of low-dose statine with ezetimibe preserve post-fatload endothelial function But: small studies

25. The PostprAndial eNdothelial function After Combination of Ezetimibe and simvAstatin (PANACEA) Study

26. Primary objective: To evaluate the effect of simvastatin/ezetimibe or high-dose simvastatin alone on fasting and postprandial endothelial function as measured with FMD and EndoPat in obese patients with metabolic syndrome.

27. The PostprAndial eNdothelial function After Combination of Ezetimibe and simvAstatin (PANACEA) Study Study design: Randomized, double blind 2 period cross-over 100 patients 5 centers in The Netherlands and Spain 6 weeks simvastatin 80mg 6 weeks simvastatin/ezetimibe 10/10mg

28. PANACEA trial design A BB A A B Parallel study Cross-over study

29. Conclusions Non-fasting triglycerde plasma levels are associated with increased CVD risk In the postprandial phase HDL-c plasma levels drop Postprandial hyperlipidemia can be reduced with lipid- lowering therapy Postprandial endothelial dysfunction can be diminished by lipid-lowering therapy Although an appealing pathophysiological concept, the clinical usefulness of postprandial hyperlipidemia remains to be determined