Ezetrol(tm) with a Statin - Achieves Greater LDL Cholesterol Reduction Compared with Statin Therapy Alone

Main Category: Statins
Article Date: 25 Apr 2005 - 11:00 PST

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Results from two clinical trials showed that co-administration of EZETROL(tm) (ezetimibe) with ongoing statin therapy (simvastatin or atorvastatin), provided greater reduction in LDL ("bad") cholesterol in hypercholesterolemia patients with coronary heart disease (CHD) compared with statin therapy alone (ezetimibe/simvastatin 74.3 percent vs. placebo/simvastatin 16.7 percent; p¡Ü0.001; ezetimibe/atorvastatin 81.3 percent vs. placebo/atorvastatin 21.8 percent; p¡Ü0.001).1,2 In addition, the study demonstrated that significantly more patients taking EZETROL with ongoing statin therapy achieved European and U.S. LDL-cholesterol (LDL-C) level guidelines (¡Ü2.60 mmol/L or ¡Ü100 mg/dl), compared with statin therapy alone. EZETROL used with a statin provides Dual Inhibition of two sources of cholesterol by inhibiting the production of cholesterol mainly in the liver and inhibiting the absorption of cholesterol in the intestine. This data confirms that treating two sources of cholesterol results in greater LDL-C reduction, and allows significantly more patients to reach greater goal attainment versus statin therapy alone.

Co-administration of EZETROL with simvastatin provides greater cholesterol goal attainment

The first study involved 372 male and female patients (aged ¡Ý18 years) with CHD and on stable dose simvastatin 10 or 20 mg for at least six weeks. After a four week simvastatin 10 or 20 mg plus placebo and diet run-in period, eligible patients (LDL-C >2.60 mmol/L and ¡Ü4.20 mmol/L and triglycerides ¡Ü4.00 mmol/L), were randomized into a double blind comparative study with EZETROL 10 mg co-administered with ongoing simvastatin 10 or 20 mg (n=181), versus placebo, to match EZETROL co-administration with simvastatin 10 or 20 mg (n=191) for six weeks.

The percentage of patients achieving LDL-C goal of ¡Ü2.60 mmol/L after six weeks of treatment was significantly greater with EZETROL than with placebo (74.3 percent vs. 16.7 percent; p¡Ü0.001). EZETROL was generally well tolerated compared to placebo with on-going simvastatin treatment. The results of this trial confirm that co-administering EZETROL with ongoing simvastatin therapy provides significantly greater lowering of LDL-C through Dual Inhibition of two sources of cholesterol, thus allowing a greater number of patients to reach cholesterol goal attainment.

EZETROL co-administered with atorvastatin provides greater cholesterol goal attainment

The second study involved 450 male and female patients (aged ¡Ý18 years) with CHD who had not achieved an LDL-C goal of ¡Ü2.60mmol/L while on stable dose atorvastatin 10 or 20 mg for at least six weeks.2 Patients with LDL-C levels between >2.60 mmol/L and ¡Ü4.20 mmol/L were stratified according to atorvastatin dose and randomized in equal proportions following a four week diet/placebo run in period, to receive once-daily oral treatment with EZETROL 10 mg (n=220) or placebo (n=230). Both randomized arms received treatment for six weeks while continuing their open-label atorvastatin therapy.

The percentage of patients who achieved the LDL-C goal of ¡Ü2.60 mmol/L was significantly greater with EZETROL than placebo (81.3 percent vs. 21.8 percent; p¡Ü0.001). Additionally, compared to placebo, co-administration of EZETROL with ongoing atorvastatin therapy also led to significantly larger mean percentage reductions from baseline in LDL-C (31.2 percent vs. 4.2 percent; p¡Ü0.001). Total cholesterol, triglycerides, non-HDL-C, and apolipoprotein B were significantly reduced (p¡Ü0.001), and HDL-C was significantly increased (p¡Ü0.05) after six weeks with EZETROL compared to placebo.

Defining two sources of cholesterol

Cholesterol in the body originates from two main sources: production by hepatic and extra hepatic tissues and absorption in the intestine. Cholesterol-lowering agents (statins) reduce cholesterol levels through single inhibition of one pathway; that is, by inhibiting the synthesis (production) of cholesterol in the liver. EZETROL (ezetimibe), the first specific cholesterol absorption inhibitor, works by inhibiting intestinal absorption of cholesterol. This cholesterol comes from both dietary sources (food) and, predominantly, the cholesterol recirculated in the bile. Combined treatment with a statin and EZETROL initiates highly effective dual inhibition of harmful cholesterol by targeting both of the main sources in the body, production and absorption, thus providing significantly greater reduction of LDL-C plasma levels.

About EZETROL

EZETROL (ezetimibe), a cholesterol absorption inhibitor, has been developed and is being marketed by Merck & Co., Inc. (NYSE:MRK) and Schering-Plough Corporation (NYSE:SGP) in connection with a partnership formed by both companies to develop and market worldwide (excluding Japan) new prescription medicines in cholesterol management. In Europe, ezetimibe is indicated for treatment in:

-- primary hypercholesterolemia, co-administered with statins, as adjunctive therapy to diet in patients with primary (heterozygous familial and non-familial) hypercholesterolemia not appropriately controlled with a statin alone;

-- monotherapy as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolemia in whom a statin is considered inappropriate or is not tolerated;

-- homozygous familial hypercholesterolemia (HoFH), co-administered with a statin, as adjunctive therapy to diet for use in patients with HoFH, who may also receive adjunctive treatments (e.g., LDL apheresis); and

-- homozygous sitosterolemia (phytosterolemia) as adjunctive therapy to diet for use in patients with homozygous familial sitosterolemia.

The product has been approved in more than 70 countries around the world, including the United States, where the Food and Drug Administration approved it on 25 October 2002, and it is marketed as ZETIA(tm). Ezetimibe has a favorable tolerability profile, which is maintained over long-term therapy. Studies demonstrate that ezetimibe co-administered together with a statin is well tolerated, and has an overall tolerability profile comparable to statin monotherapy.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines in over 20 therapeutic categories. The company also devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit http://www.merck.com

About Schering-Plough

Schering-Plough Corporation is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough's vision is to earn the trust of the physicians, patients and customers served by its more than 30,000 people around the world. The company is based in Kenilworth, N.J., and its Web site is http://www.schering-plough.com.

References:

1. M Farnier et al; Effect of co-administering ezetimibe with on-going simvastatin treatment on LDL-C goal attainment in CHD patients with hypercholesterolemia; 2005 Annual Meeting of the European Atherosclerosis Society (EAS) - 24 April 2005 - Poster

2. Jose M. Cruz Fernandez et al; Efficacy and safety of ezetimibe co-administered with ongoing atorvastatin therapy in achieving low-density lipoprotein goal in patients with hypercholesterolemia in coronary heart disease; 2005 Annual Meeting of the European Atherosclerosis Society (EAS) - 24 April 2005 - Poster

Laura Mitchell
Healthcare and Pharmaceuticals
Hill & Knowlton (UK) Ltd
20 Soho Square
London
W1A PR1
t: +44 (0)20 7413 3015
f: +44 (0)20 7413 3112
lmitchell@hillandknowlton.com

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