ezetimibe and simvastatin in primary hypercholesterolemia, diabetes mellitus type 2, and coronary heart disease (completed)

Conditions: Hypercholesterolemia; Diabetes Mellitus, Type 2; Coronary Disease

Summary: 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.


Eligibility criteria:
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 (glycated hemoglobin \[hba1c\] \<=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 (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 (thyroid stimulating hormone \[tsh\] 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 human immunodeficiency virus (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.