Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia

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Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia The ENHANCE trial ClinicalTrials.gov number: NCT00552097 John J.P. Kastelein, MD, PhD* Department of Vascular Medicine Academic Medical Center Amsterdam, The Netherlands *On behalf of all ENHANCE investigators Kastelein, et al, N Eng J Med 2008; In Press Adapted from ACC 2008.

Presenter Disclosure Information John J.P. Kastelein, MD, PhD The following relationships exist related to this presentation: Dr. Kastelein consults for Merck & Schering Plough Dr. Kastelein is also a consultant for several other pharmaceutical companies with lipid-lowering agents. Adapted from ACC 2008.

Although the authors allowed the sponsors to review the manuscript and the presentation, all data analyses and interpretation of the results are those of the academic investigators. Adapted from ACC 2008.

Background Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of LDL-c when added to statin treatment. However, the effect of Ezetimibe on the progression of atherosclerosis is unknown Adapted from ACC 2008.

ENHANCE logical next step after ASAP Timeline 1995 2000 2005 2010 LIPID (pediatric) ASAP ENHANCE Simvastatin 80 mg + Ezetimibe 10 mg Versus Pravastatin 20-40 mg Versus Placebo Atorvastatin 80 mg Versus Simvastatin 40 mg 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 Adapted from ACC 2008.

ENHANCE Study Design Simvastatin 80 mg 24 3 6 9 12 15 18 21 RANDOMI ZAT I ON 24 Months 3 6 9 12 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 Adapted from ACC 2008.

ENHANCE Study Population Major inclusion criteria Major exclusion criteria Age 30-75 years HeFH: Genotyping Diagnostic criteria WHO Untreated LDL-C levels > 210 mg/dL (5.43 mmol/l) Patients on lipid-lowering treatment LDL-c after wash –out > 210 mg/dL High-grade carotid stenosis History carotid endarterectomy Carotid stenting Congestive heart failure III/IV Adapted from ACC 2008.

ENHANCE cIMT Methodology Carotid Intima-Media thickness (cIMT) measurements Measurements were made at a predefined angle of insonation Only the far-walls of all segments were imaged Images were stored in DICOM for offline image analyses de Groot E, et al. Circulation. (2004) 109[Suppl III]:III-33-III-38. Adapted from ACC 2008.

Baseline Characteristics Simvastatin Monotherapy Simvastatin plus Ezetimibe All randomized patients n=363 n=357 P-value Age (yr) 45.710.0 46.19.0 0.69 Male sex no. (%) 179(49%) 191 (54%) 0.26 Body-mass index 26.74.4 27.44.6 0.047 History of diabetes 5(1%) 8 (2%) 0.38 Hypertension 51 (14%) 67 (19%) 0.09 Current smoking 104 (29%) 102 (29%) 0.98 History of MI 26 (7%) 14 (4%) 0.06 Prior use of statins 297 (82%) 286 (80%) 0.56 Systolic mm Hg 12415 12515 0.31 Diastolic mm Hg 7810 789 0.41 Adapted from ACC 2008.

Percentage change from baseline -16.5 % incremental reduction LDL-cholesterol Baseline (mg/dL) 24 months (mg/dL) Simva 318 ± 66 193 ± 60 Eze-Simva 319 ± 65 141 ± 53 10 -10 -20 -30 P<0.01 Percentage change from baseline -40 -16.5 % incremental reduction -50 -60 -70 6 Simva Eze-Simva 12 18 24 Months Adapted from ACC 2008.

Other Lipids and Apolipoproteins Percent Change From Baseline Simvastatin 80 EZE/simva 10/80 P value Total Cholesterol -31.9±0.8 -45.3±0.8 <0.01 LDL-cholesterol -39.1±0.9 -55.6±0.9 Triglycerides (median) -23.2 -29.8 HDL-cholesterol 7.8±0.9 10.2±1.0 0.05 Apo B -33.1±0.9 -46.7±0.9 Apo A1 6.9±0.8 6.3±0.8 0.56 Adapted from ACC 2008.

-26 % incremental reduction hsCRP Baseline 24 months (mg/L) (mg/L) Simva 1.7(0.8-4.1) 1.2(0.6-2.4) Eze-Simva 1.7(0.8-3-9) 0.9(0.5-1.9) Median percent change from Baseline P< 0.01 3 6 12 18 24 Months 10 -10 -20 -30 -40 -50 -60 -70 -80 -26 % incremental reduction Simva Eze-Simva Adapted from ACC 2008. 12

Primary Efficacy Outcome Adapted from ACC 2008.

Simvastatin Monotherapy Simvastatin plus Ezetimibe No significant changes in 1° or 2° endpoints Variable Simvastatin Monotherapy Simvastatin plus Ezetimibe P value (mean) Mean Median Millimeters Baseline n=342 n=338 Mean cIMT 0.700.13 0.69 0.690.13 0.68 0.64 Mean maximum cIMT 0.800.16 0.78 0.800.17 0.76 0.94 24 months follow-up n=320 n=322 0.700.14 0.710.15 0.29 0.81±0.17 0.79 0.82±0.18 0.27 Difference from baseline 0.00580.0037 0.0095 0.01110.0038 0.0058 0.01030.0049 0.0103 0.01750.0049 0.0160 consistent inferential results observed for non-parametric (median) and parametric (mean) analyses Adapted from ACC 2008.

Simvastatin Monotherapy Simvastatin plus Ezetimibe Variable Simvastatin Monotherapy Simvastatin plus Ezetimibe P value (mean) Mean Median Millimeters Baseline n=342 n=338 CCA 0.680.16 0.66 0.670.16 0.64 0.45 CBA 0.800.20 0.78 0.790.22 0.76 0.51 ICA 0.610.17 0.58 0.620.17 0.60 0.42 24 months follow-up n=320 n=322 0.680.15 0.93 0.810.22 0.79 0.810.23 0.77 0.37 0.59 0.640.17 0.21 Difference from baseline 0.00240.0043 0.0043 0.00190.0044 0.0010 0.00620.0069 0.0099 0.01440.0070 0.0107 -0.00070.0064 0.0057 0.00990.0065 0.0066 consistent inferential results observed for non-parametric (median) and parametric (mean) analyses Adapted from ACC 2008.

Mean cIMT during 24 months of therapy Longitudinal, repeated measures analysis 6 12 18 24 0.60 0.70 0.75 0.80 0.65 Months P=0.88 Mean IMT (mm) Simva Eze-Simva Adapted from ACC 2008.

No Significant Changes Across any Subgroup Progression Change cIMT (mm) Regression Adapted from ACC 2008.

Discussion Adapted from ACC 2008.

Measurement Technique Possible explanations for the absence of an incremental reduction in cIMT Measurement Technique Technique not accurate enough to reflect changes in atherosclerotic burden? The Compound Ezetimibe lacks vascular benefit despite the observed LDL-c and hsCRP reduction The Population At too low a risk to detect changes, which would limit the ability to detect a differential response Adapted from ACC 2008.

Quality of cIMT measurement Completeness Percentage Number of images Mean cIMT 88 % 20986/23856 Mean CCA 97 % 7681/7952 Mean CIA 83 % 6603/7952 Mean CBA 84 % 6702/7952 Intraclass correlation coefficient at baseline: 0.93 Intraclass correlation coefficient at study endpoint: 0.95 Standard deviation between the paired measure at baseline: 0.053 mm Standard deviation between the paired measure at 24 months: 0.056 mm Adapted from ACC 2008.

The Compound Ezetimibe no pleiotropic effects? Simvastatin 10 mg group Baseline 4 weeks Baseline 4 weeks Flow dependent dilation (percent change of diameter) P<0.01 P= n.s. 3 6 9 12 Chronic heart failure patients (NYHA III), n=10 per group LDL-c reduction similar in both groups. Simvastatin: 15.6 % Ezetimibe: 15.4% Ezetimibe 10 mg group Landmesser et al, Circulation 2005; 111(18): 2280-1 Adapted from ACC 2008.

Pleiotropic Effects of Statins: Benefit Beyond Cholesterol Reduction? Robinson et al, J Am Coll Cardiol 2005;46:1855-62 Adapted from ACC 2008.

The treatment of patients with FH has witnessed profound changes The Population The treatment of patients with FH has witnessed profound changes Adapted from ACC 2008. 23

Baseline cIMT in LIPID (pediatric), ASAP and ENHANCE 0.4 0.8 1.2 1.6 2.0 ENHANCE ASAP Frequency Mean CIMT (mm) 2.4 LIPID (pediatric) Baseline mean cIMT (mm) LIPID (pediatric) 0.495±0.050 ASAP 0.92±0.20 ENHANCE 0.70±0.13 Adapted from ACC 2008.

Ezetimibe-Simvastatin Safety Observations Both regimens well tolerated, with overall safety profiles generally similar and consistent with product labels One case of viral hepatitis A in the simvastatin-only arm One case of myopathy (defined as CPK > 10 ULN, with associated muscle symptoms) in the simvastatin-only arm and 2 cases in the Ezetimibe-Simvastatin arm Consecutive Simvastatin Ezetimibe-Simvastatin P n=360 n=356 ALT and/or AST ≥ 3 X ULN 8 10 0.62 CPK ≥ 10 X ULN 4 0.25 Subjects with 2 consecutive measurements for ALT and/or AST; a single last measurement ≥ 3 ULN; a measurement ≥ 3 X ULN followed by < 2 ULN that was taken more than 2 days after the last dose of study medication. Adapted from ACC 2008.

Conclusion The addition of Ezetimibe to Simvastatin did lead to expected changes in LDL-c and hsCRP, but did not reduce any cIMT parameter The reason(s) for this discrepancy currently remains unknown Adapted from ACC 2008.