This multicenter, randomized, double-blind, placebo-controlled study will assess, after 6
weeks of dosing, whether co-administration of ezetimibe 10 mg with simvastatin 20 mg will be
more effective than treatment with doubling the dose of simvastatin to 40 mg alone in
reducing low-density lipoprotein-cholesterol (LDL-C) concentrations and in achieving the
National Cholesterol Expert Panel (NCEP) III LDL-C target goal of <2. 6 mmol/L (<100 mg/dL)
for subjects with diabetes mellitus and coronary heart disease.
Inclusion Criteria:
- Subject must have diabetes mellitus type 2 (fasting plasma glucose >7 mmol/L [126
mg/dL]) of at least 12 months duration at Visit 3 and must be adequately controlled
(HbA1c <=9. 0%). Subjects must not have had a change in antidiabetic pharmacotherapy
[i. e. changes in dosage (with the exception of +/- 10 units of insulin) or addition of
new medication] or experience recent history of repeated hypoglycemia or unstable
glycemic control within 3 months of Visit (Baseline Visit).
- Subjects must have documented coronary heart disease (CHD). For the purposes of this
study, CHD will include one or more of the following features: documented stable
angina with evidence of ischemia on exercise testing); history of myocardial
infarction; history of percutaneous transluminal coronary intervention (primarily PCTI
with or without stent placement); symptomatic peripheral vascular disease
(claudication); documented history of atherothrombotic cerebrovascular disease; and/or
documented history of unstable angina or non-Q wave myocardial infarction.
- Subjects must have a low-density lipoprotein cholesterol (LDL-C) concentration >=2. 6
mmol/L (100 mg/dL) to <=4. 1 mmol/L (160 mg/dL) using the Friedewald calculation
available at the time of randomization Visit 3 (Baseline Visit).
- Subjects must have triglyceride concentrations of <3. 99 mmol/L (350 mg/dL) at Visit 3
(Baseline Visit).
- Subject must be currently taking simvastatin 20 mg daily and by history has taken 80%
of daily evening doses for the 6 weeks prior to Visit 3 (Baseline Visit).
- Subject must be >=18 years and <=75 years of age.
- Subjects must have maintained a cholesterol lowering diet and exercise program for at
least 4 weeks prior to Screening (Visit 2) and be willing to continue the same diet
and exercise program during the study.
- Subjects must have liver transaminases (alanine aminotransferase [ALT], aspartate
aminotransferase [AST]) <50% above the upper limit of normal, with no active liver
disease, and creatinine kinase (CK)<50% above the upper limit of normal at Visit 3
(Baseline Visit).
- Clinical laboratory tests (complete blood count (CBC), blood chemistries, urinalysis)
must be within normal limits or clinically acceptable to the investigator at Visit 3
(Baseline Visit).
- Subjects must report a stable weight history for at least 4 weeks prior to entry into
study at Visit 3 (Baseline Visit).
- Women receiving hormonal therapy, including hormone replacement, any estrogen
antagonist/agonist, or oral contraceptives, must have been maintained on a stable dose
and regimen for at least 8 weeks and be willing to continue the same regimen for the
duration of the study.
- Women of childbearing potential (includes women who are less than 1 year
postmenopausal and women who become sexually active) must be using an acceptable
method of birth control (e. g., hormonal contraceptive, medically-prescribed
intrauterine device (IUD), condom in combination with spermicide) or be surgically
sterilized (e. g., hysterectomy or tubal ligation).
- Subjects must be free of any clinically significant diseases other than diabetes
mellitus or coronary heart disease that would interfere with study evaluations.
- Subjects must understand and be able to adhere to the dosing and visit schedules, and
must agree to remain on their cholesterol-lowering diet and their exercise regimen for
the duration of the study
- Subjects must demonstrate their willingness to participate in the study and comply
with its procedures by signing a written informed consent.
Exclusion Criteria:
- Subjects whose body mass index (BMI = weight[kg]/height[m]**2) is >=35 kg/m**2 at
Visit 3 (Baseline Visit).
- Subjects who consume >14 alcoholic drinks per week. (A drink is: a can of beer, glass
of wine, or single measure of spirits).
- Any condition or situation which, in the opinion of the investigator, might pose a
risk to the subject or interfere with participation in the study.
- Women who are pregnant or nursing.
- Congestive heart failure defined by New York Heart Association (NYHA) as Class III or
IV.
- Uncontrolled cardiac arrhythmia.
- Myocardial infarction, acute coronary insufficiency, coronary artery bypass surgery,
or angioplasty within 3 months of Visit 3 (Baseline Visit).
- Unstable or severe peripheral artery disease within 3 months of Visit 3 (Baseline
Visit).
- Newly diagnosed or currently unstable angina pectoris.
- Uncontrolled hypertension (treated or untreated) with systolic blood pressure >160
mmHg or diastolic >100 mmHg at Visit 3 (Baseline Visit).
- Uncontrolled endocrine or metabolic disease known to influence serum lipids or
lipoproteins, i. e., secondary causes of hyperlipidemia, such as secondary
hypercholesterolemia due to hypothyroidism (TSH above upper limit of normal) at Visit
3. Subjects with a history of hypothyroidism who are on a stable therapy of thyroid
hormone replacement for at least 6 weeks are eligible for enrollment if TSH levels are
within normal limits at Visit 3 (Baseline Visit).
- Impaired renal function (creatinine >2. 0 mg/dL) or nephrotic syndrome at Visit 3
(Baseline Visit).
- Disorders of the hematologic, digestive, or central nervous systems including
cerebrovascular disease and degenerative disease that would limit study evaluation or
participation.
- Known HIV positive.
- Cancer within the past 5 years (except for successfully treated basal and squamous
cell carcinomas).
- History of mental instability, drug/alcohol abuse within the past 5 years, or major
psychiatric illness not adequately controlled and stable on pharmacotherapy.
- Subjects who have not observed the designated wash-out period for any of the
prohibited medications.
- Subjects currently consuming large amounts of grapefruit juice (>1 liter/day).
- Oral corticosteroids, unless used as replacement therapy for pituitary/adrenal disease
and the subject is on a stable regimen for at lest 6 weeks prior to Visit 3 (Baseline
Visit).
- Subjects who are currently using cardiovascular medication (e. g., antihypertensive,
antiarrhythmic) and have not been on a stable regimen for at least 6 weeks prior to
Visit 3 (Baseline Visit) and it is expected to change during the study.
- Subjects who are currently using psyllium, other fiber-based laxatives, and/or any
other over-the-counter (OTC) therapy known to affect serum lipid levels (phytosterol
margarine), and have not been on a stable regimen for at least 5 weeks prior to study
entry Visit 3 (Baseline Visit) and who do not agree to remain on this regimen
throughout the study.
