Clinical experience with ezetimibe/simvastatin in a Mediterranean population The SETTLE Study I. Migdalis a, A. Efthimiadis b, St. Pappas c, D. Alexopoulos d, F. Vlasserou e and D. P. Mikhailidis f a 2nd Department of Internal Medicine, NIMTS General Hospital, Athens, Greece b Cardiology Department, Hippokration General Hospital, Thessaloniki, Greece c 3rd Department of Internal Medicine, NIKAIA General Hospital, Athens, Greece d Cardiology Department, University Hospital of Rion, Patras, Athens, Greece e Medical Department, VIANEX Pharmaceuticals SA, Athens, Greece f Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Campus, University College

2 SETTLE Study S imvastatin E zetimibe T herapy to T arget L ipids E levation Background  Elevated plasma low-density lipoprotein cholesterol (LDL-C) is a pivotal risk factor in the development of atherosclerotic coronary heart disease (CHD).  Optimal management of plasma LDL-C levels is the primary goal of therapeutic intervention in patients at risk of coronary events.

3 SETTLE Study Objective  In hypercholesterolemic patients with LDL-C out of goal, despite prior use of statin monotherapy, to evaluate the efficacy of switching to ezetimibe/ simvastatin (EZE/SIMVA) 10/20 mg or 10/40 mg.  To record CHD risk factors of hypercholesterolemic patients in Greece and observe the routine clinical practice of the use of ezetimibe / simvastatin

4 SETTLE Study: Patients  The study was conducted at 100 sites all over Greece and included 1514 patients.  Male or female mean age: 60 yrs.  LDL-C out of goal, according to physician’s evaluation at screening visit  All patients were previously treated with statin monotherapy 53.4% 46.6% male female

5 SETTLE Study: Patients The number of patients who had three risk factors or at least one CHD equivalent medical condition was 889 (58%) % Diabetes Mellitus 29.9% Hypertension 61.2% Obesity 25.6% Angina 10.5% Myocardial infarction 12.4% Revascularization procedure 14.1% Stroke or peripheral arteriopathy 6.8% Congestive heart failure 2.9% Smoking 31.1% Ex-smoking 15.7% PATIENTS CO-MORBIDITIES / RISK FACTORS

6 Primary  % patients achieving LDL-C at study endpoint (post therapy, Visit 2) Secondary  Mean % change in LDL-C, TC, TG, HDL-C at study endpoint (post therapy)  Tolerability (monitoring of adverse experiences) SETTLE Study: Efficacy Endpoints

7  This was a Phase IV, multi-center, observational study SETTLE Study: Study Design No Washout 2 Week 8 Visit 1 Week 0 Visit Screening Eze/Simva 10/20 mg/day (n=1074) Eze/Simva 10/40 mg/day (n=440) Patients prior statin monotherapy: Simvastatin 20 or 40 mg Atorvastatin 10 or 20 mg Pravastatin 40 mg Fluvastatin 80 mg Rosuvastatin 5 mg

8 SETTLE Study: Efficacy Parameters at Study Endpoint Efficacy Parameter (mg/dl) Changes in Lipid variables during the study VISIT 1 Baseline Mean (± sd) VISIT 2 Baseline Mean (± sd) MEAN CHANGE (%)p-Value LDL-C164 (31)107 (24)-33  TC248 (37)182 (29)-26  HDL-C45 (11)48 (10)10NS TG † 174 (80)137 (49) non-HDL-C203 (38)134 (29)-32 

9 SETTLE Study: Efficacy Parameters at Study Endpoint Changes in Lipid variables during the study (mean of absolute values, mg/dl) TC LDL-C TG HDL-C 56.8 mg/dl 66.7 mg/dl 37.1 mg/dl 3 mg/dl

10 SETTLE Study: % of Patients Reaching LDL-C Goals at Study Endpoint 26.2% At Goal Not at Goal (n=397) (n=1117) 73.8%

11 Adverse experiences In 18 patients, 23 adverse experiences were reported (1.2%) Most of them were mild and expected (dizziness, rash, myalgia, GI symptoms, CPK increase in 2 patients, aminotransferase increase in 3 patients) There was one serious AE, which was NOT related to the study treatment. There was no difference in patients, at or NOT at goal. There was statistical difference in patients administered INEGY 10/20 or 10/40 mg There was no difference in patients more or less than 65 years old.

12  In patients taking a stable dose of statin monotherapy, switching to EZE/SIMVA 10/20 mg or 10/40 mg resulted in:  Significantly greater reductions in LDL-C, TC, TG and non-HDL- C, (p  0.001)  More patients achieving LDL-C goal, as this was determined by their attending physician (p  0.001)  In the routine clinical care setting, the safety/tolerability profile of EZE/SIMVA was favorable  The present study showed that switching from statin monotherapy to EZE/SIMVA 10/20 mg or 10/40 mg provides greater reductions in LDL-C, resulting in clinically significant increases in the proportion of high-risk patients achieving LDL-C goals. SETTLE Study: Summary of Results

13  In our Mediterranean population, the combination of EZE / SIMVA appears to be an appropriate and safe treatment option for patients who cannot achieve the LDL-C target with statin monotherapy SETTLE Study: Conclusion