1. New Approaches to LDL Reduction Cholesterol Absorption Inhibitors

2. Inhibition of Cholesterol Absorption and Production With Ezetimibe/Simvastatin 2 Simvastatin Extrahepatic tissues Dietary cholesterol Liver synthesis Excretion 1000 mg/day Absorption ~300 mg/day–700 mg/day Intestine Ezetimibe Biliary cholesterol ~1000 mg/day

3. 3 Peripheral cells Liver Diet Feces DuodenumJejunumIleum Bile LDL Forward pathway VLDLLDL HDL Reverse pathway Cholesterol Balance in Mice (µmol/day.100 g body wt) 7 2 4 5 10 5

4. 4 Ezetimibe strongly increases TICE TICE (re)absorption bile Diet Feces Control + Ezetimibe Control Ezetimibe Control Ezetimibe Control Ezetimibe Control Ezetimibe

5. 5 Peripheral cells Liver Diet Feces DuodenumJejunumIleum Bile VLDLLDL HDL LDL Forward pathway Reverse pathway 400 1000 700 1000 300 Cholesterol Fluxes in Humans (mg/day.70 kg body wt)

6. 6 Next Steps Assessment of direct intestinal cholesterol excretion in vivo in humans. Determine the contribution of TICE in low and high absorbers Test the effect of pharmacological manipulation in humans.

7. 7 Cholesterol Absorption Inhibitors Lower LDL-C and that is Enough in Itself

8. 8 ENHANCE

9. ENHANCE - Logical Next Step After ASAP - 9 LIPID (pediatric) Atorvastatin 80 mg Versus Simvastatin 40 mg ASAP Simvastatin 80 mg + Ezetimibe 10 mg Versus Simvastatin 80 mg ENHANCE Timeline 2000 2010 1995 2005 Pravastatin 20-40 mg Versus Placebo Wiegman et al, Efficacy and Safety of Statin Therapy in Children With FH. JAMA 2004; 292(3):331-7 Smilde et al, Atorvastatin versus Simvastatin on Atherosclerotic Progression study. Lancet 2001;357:577-81

10. ENHANCE Study Population 10 Major inclusion criteria  HeFH: Genotyping Diagnostic criteria WHO  Age 30-75 years  Untreated LDL-C levels > 210 mg/dL (5.43 mmol/l)  Patients on lipid-lowering treatment LDL-c after wash –out > 210 mg/dL (5.43 mmol/l) Major exclusion criteria  High-grade carotid stenosis  History carotid endarterectomy  Carotid stenting  Congestive heart failure III/IV NO MINIMAL CAROTID IMT ENTRY CRITERIA Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43

11. 11 ENHANCE Study Design Simvastatin 80 mg RANDOMIZATIONRANDOMIZATION 0 24 Months 3 6912 15 18 21 Pre-randomization Phase FH: LDL-c ≥ 210 mg/dL Screening and Fibrate Washout Placebo Lead- In/ Drug Washout Weeks -6 -10 to -7 Ezetimibe 10 mg-Simvastatin 80 mg IMT assessment

12. Baseline Characteristics 12 Simvastatin Monotherapy Simvastatin plus Ezetimibe All randomized patientsn=363n=357P-value Age (yr) 45.7  10.046.1  9.0 0.69 Male sex no. (%)179(49%)191 (54%)0.26 Body-mass index 26.7  4.427.4  4.6 0.047 History of diabetes5(1%)8 (2%)0.38 Hypertension51 (14%)67 (19%)0.09 Current smoking104 (29%)102 (29%)0.98 History of MI26 (7%)14 (4%)0.06 Prior use of statins297 (82%)286 (80%)0.56 Systolic mm Hg 124  15125  15 0.31 Diastolic mm Hg 78  1078  9 0.41 Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43

13. 13 Months LDL-Cholesterol Simva Eze-Simva - 40 06 12 18 24 - 50 - 60 - 70 0 - 10 - 20 - 30 10 Percentage change from baseline P<0.01 -16.5 % incremental reduction Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43 Baseline (mg/dL) 24 months (mg/dL) Simva318 ± 66193 ± 60 Eze-Simva319 ± 65141 ± 53 -40% -56% Decrease (%)

14. 14 ENHANCE hsCRP Simva Eze-Simva Median percent change from Baseline p < 0.01 3 6 12 18 24 Months 10 -10 -20 -30 -40 -50 -60 -70 -80 0 -26 % incremental reduction Baseline (mg/L) 24 months (mg/L) Simva1.7 (0.8-4.1)1.7(0.8-3.9) Eze-Simva1.2(0.6-2.4)0.9(0.5-1.9)

15. Mean cIMT During 24 Months of Therapy Longitudinal, Repeated Measures Analysis 15 Mean IMT (mm) Simva Eze-Simva 6 1218 24 0.60 0.70 0.75 0.80 0.65 Months P=0.88 Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43

16. Possible Explanations for the Absence of an Incremental Reduction in cIMT 16 Measurement Technique Technique not accurate enough to reflect changes in atherosclerotic burden? The Population At too low a risk to detect changes, which would limit the ability to detect a differential response The Compound Ezetimibe lacks vascular benefit despite the observed LDL-c and hsCRP reduction

17. 17 The Trial Design and Population To have any chance of success using cIMT to demonstrate that one treatment is better than another one of two critical factors must be present – preferably both: The ‘control’ group must show significant progression – if not then only significant regression in the ‘test’ group can result in a positive trial The population studied must have significant and quantifiable lipid rich intima – if minimal or no significant atherosclerosis is present then only possible change to be assessed is progression

18. Critical Factors for Successful cIMT Trial 18 regression progression regression progression cIMT mm years 012 0.80 0.85 0.75 0.90 0.95 0.70 0.65 ASAP - 1997 ASAP Simva LDLc -40% Atorva LDLc -52% Simva/Control progressed; atorva/Test stable/regressed SUCCESS!! P <0.05

19. Critical Factors for Successful cIMT Trial 19 regression progression regression progression cIMT mm years 012 0.80 0.85 0.75 0.90 0.95 0.70 0.65 ASAP - 1997 ENHANCE - 2003 ENHANCE Simva LDLc -40% Simva/Eze LDLc -57% ASAP Simva LDLc -40% Atorva LDLc -52% P= ns

20. ASAP and ENHANCE Baseline cIMT in LIPID (Pediatric) 20 LIPID (pediatric) 0.4 0.81.21.62.0 ENHANCE ASAP Frequency Mean CIMT (mm) 2.4 Baseline mean cIMT LIPID (pediatric)0.495±0.050 ASAP0.92±0.20 ENHANCE0.70±0.13

21. What About the Trial Indicating Potential Harm from Increased CVD Events? 21 Although ENHANCE was a relatively small trial in low risk FH patients was there any evidence from the CVD events that addition of ezetimibe caused harm? Can one even pick up such a signal from such small trials as ENHANCE in this FH population?

22. CVD Events – Recent FH cIMT Trials: RADIANCE I (CETPi) and CAPTIVATE (ACATi) 22 Incidence of CVD events (%)AtorvaAtorva + TorcetStatinStatin+ ACATi (n=454)(n=450)(n=438)(n=443) CVD death/MI/ Revasc/Stroke11 (2.4%)23 (5.1%)`15 (3.4%)28 (6.3%)` RADIANCE I *Kastelein et al NEJM 2007; 356:1620-30 **Meuwese MC et al JAMA in press CAPTIVATE `p<0.05 Thus even small studies (700-900 patients) in FH appear to be able to detect potential CVD harm `p<0.02

23. Conclusion from ENHANCE 23 While the results of ENHANCE have been less than optimal for the sponsors of the trial they actually carry very good news for those with FH, and all patients on long term lipid lowering therapy, in that the data would seem to strongly indicate that even moderate, long term LDLc lowering dramatically reduces the atherosclerotic burden, at least in carotid arteries, and virtually halts progression of the underlying disease.