The purpose of this study is to investigate whether low-dose simvastatin in combination with
ezetimibe in comparison to high-dose simvastatin alone, has a beneficial effect on the
function of the endothelium after an oral fat load in patients with the metabolic syndrome.
INCLUSION CRITERIA:
1. Patient has a diagnosis of metabolic syndrome according to the modified 2005 AHA/NHLBI
Scientific Statement with at least:
- Abdominal obesity defined as:
- Males: waist circumference >102 cm (>40 in) Note: For male Asian Americans
(as reported by the patient), waist circumference >90 cm (>35 in)
- Females: waist circumference >88 cm (>35 in) Note: For female Asian
Americans (as reported by the patient), waist circumference >80 cm (>31 in)
and two of the following 4 other criteria for the metabolic syndrome:
- Triglycerides (TG) > 150 mg/dL (> 1. 7 mmol/L)
- HDL Cholesterol
- Males: HDL-C < 40 mg/dL (< 1. 03 mmol/L)
- Females: HDL-C < 50 mg/dL (< 1. 3 mmol/L)
- Blood pressure
- Systolic Blood Pressure ≥ 130 mm Hg or
- Diastolic Blood Pressure ≥ 85 mm Hg
- Fasting glucose ≥ 100 mg/dL (≥ 5. 55 mmol/L)
2. Patient understands the study procedures, alternative treatments available, and risks
involved with the study, and voluntarily agrees to participate by giving written
informed consent.
3. Patient is a male or female of 18-79 years of age on the day of signing informed
consent.
4. Patient is a non-smoker. Non-smoker is defined as someone who never smokes or has not
smoked > 1 year prior to Visit 1.
5. Patient is willing to maintain a stable diet for the duration of the study.
6. Patient is a postmenopausal female who is not receiving hormone therapy (including
cyclic and non-cyclical hormone replacement therapy or any estrogen
antagonist/agonist). Postmenopausal status is defined as (1) no menses for ≥1 year but
<3 years and confirmed by FSH levels elevated into the postmenopausal range (as
defined by the designated laboratory) or (2) no menses for at least 3 years.
7. Patient is naïve to lipid-lowering therapy. Naïve is defined as not being treated with
a statin, a fibrate or ezetimibe for 3 months before Visit 1 (Week - 2)
8. Patient has a baseline fasting LDL-C level of ≥ 100 mg/dL and < 220 mg/dL (≥ 2. 59
mmol/L and 5. 69 < mmol/L), and TG level < 400 mg/dL (< 4. 52 mmol/L).
EXCLUSION CRITERIA:
1. Patient has a BMI > 35.
2. Patient has hypersensitivity or intolerance to ezetimibe or simvastatin or any
component of these medications, or to latex.
3. Patient routinely consumes more than 14 alcoholic drinks per week.
4. Patient is currently participating or has participated in a study with an
investigational compound or device within 30 days of signing informed consent.
5. Patient has a smoking history > 10 pack-years (1 pack-year = at least 20 cigarettes
per day for a year) OR patient who has smoked within 3 months prior to Visit 1 (Week
- 2).
6. Patient has exclusionary laboratory values at Visit 1 (Week - 2) as listed in the table
below:
liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase
[AST]) > 1. 5 X ULN with no active liver disease Serum glucose > 7. 0 mmol/L (>126
mg/dL) Creatine kinase(CK)> 2 X ULN Albumin: creatinine ratio > 34 TSH <0. 3 mcIU/mL or
> 5. 0 mcIU/mL
7. Patient has a history or current evidence of any condition, therapy, lab abnormality
or other circumstance that might confound the results of the study, or interfere with
the patient's participation for the full duration of the study, such that it is not in
the best interest of the patient to participate.
8. It is not possible to obtain a FMD measurement of sufficient quality at screening
(Visit 1)
9. Patient has congestive heart failure.
10. Patient has atherosclerotic vascular disease. (As per NCEP ATP III and AHA/ACC
Guidelines: Established atherosclerotic vascular disease includes history of
myocardial infarction, stable angina, coronary artery procedures (angioplasty or
bypass surgery) or evidence of clinically significant myocardial ischemia. Other
atherosclerotic vascular disease includes clinical manifestations of non-coronary
forms of atherosclerotic disease (peripheral arterial disease, cerebrovascular
disease, abdominal aortic aneurysm, and carotid artery disease [transient ischemic
attacks or stroke of carotid origin or >50% obstruction of a carotid artery]).
11. Patient has acute or chronic coronary heart disease.
12. Patient has a history of pre-eclampsia < 6 years prior to Visit 1 (Week - 2).
13. Patient has had a partial ileal bypass, gastric bypass or gastric banding.
14. Patient has celiac disease or other significant intestinal malabsorption.
15. Patient has untreated and uncontrolled hypertension with systolic blood pressure >160
mm Hg or diastolic >100 mm Hg at Visit 1 (Week - 2). (Patients with untreated
hypertension and with office BP at Visit 1 and Visit 2 averaging 160/100 or less can
be enrolled). Patients using blood pressure-lowering medication are excluded.
16. Patient has estimated glomerular filtration rate (eGFR) < 30 mL/min/1. 73 m2 based on
the 4-variable (age, race, gender and creatinine) MDRD (Modification of Diet in Renal
Disease) equation at Visit 1 (as done by the central lab), history of nephrotic
syndrome or other clinically significant renal disease at Visit 1 (Week - 2).
17. Patient has uncontrolled endocrine or metabolic disease known to influence serum
lipids or lipoproteins (i. e., secondary causes of hyperlipidemia), such as hypo or
hyperthyroidism, Cushing's disease) at Visit 1 (Week - 2).
18. Patient has diabetes mellitus defined as a history of diabetes or fasting serum
glucose > 126 mg/dL.
19. Patient has disorders of the hematologic (e. g. anaemia), digestive, hepatobiliary, or
central nervous systems or other diseases that would limit or complicate study
evaluation or participation.
20. Patient is known to be HIV positive.
21. Patient has a history of malignancy ≤ 5 years prior to signing informed consent,
except for adequately treated basal or squamous cell skin cancer or in situ cervical
cancer.
22. Patient is, at the time of signing informed consent, a user of "recreational" or
illicit drugs or has had a recent history (within the last year) of drug or alcohol
abuse or dependence.
23. Patient has a history of mental instability or major psychiatric illness not
adequately controlled and stable on pharmacotherapy.
24. Patient has Raynauds Syndrome.
25. Patient has significant aortic coarctation.
26. Patient has significant deformity of fingers of either hand prohibiting use of the
same digit on both hands for ENDOPAT.
27. Patient has had a mastectomy or is going to have one during the study period.
28. Patient has a history of upper extremity thrombosis
29. Patient is known to have or has a history of Obstructive Sleep Apnea Syndrome (OSAS)
30. Patient is currently taking any antihypertensive or vasoactive medications. This
includes standard antihypertensive drug therapies and nitrates.
31. Patient is currently taking any potent inhibitor of cytochrome P450 3A4 (CYP3A4), such
as: itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV
protease inhibitors, or nefazodone.
32. Patient is currently taking therapies that could increase the risk of myopathy, such
as: verapamil, amiodarone, or trandolapril/verapamil.
33. Patient is currently taking cyclosporine, danazol or fusidic acid.
34. Patient consumes > 1 liter of grapefruit juice per day.
35. Patient has taken lipid-lowering agents including OTC supplements of fish oils
containing > 200 mg/day of EPA+DHA, red yeast rice extract, Cholestin®, bile-acid
sequestrants, HMG-CoA reductase inhibitors (statins) or ezetimibe or niacin or
fibrates taken within 3 months prior to study entry.
36. Patient is receiving treatment with systemic corticosteroids (intravenous,
intramuscular and oral steroids) or has received within 6 weeks prior to randomization
(Visit 2).
37. Patient has been on treatment with orlistat, sibutramine, rimonabant or other
anti-obesity medications within 3 months prior to study entry or is actively losing
weight.
38. Patient is currently treated with psyllium, other fiber-based laxatives, phytosterol
margarines, and/or over the counter (OTC) therapies known to affect serum lipid
levels, unless treated with a stable regimen for at least 6 weeks prior to
randomization (Visit 2) and patient agrees to remain on constant regimen for the
duration of the study.
39. Patient has taken a cyclical hormone birth control pills, or any use of cyclical
hormone replacement regimen within 8 weeks prior to randomization (Visit 2).
40. Patient is being treated with a vitamin K antagonist.
41. Patient is taking phosphodiesterase inhibitors.
42. Patient is current using marihuana for medical treatment.
Olijhoek JK, Hajer GR, van der Graaf Y, Dallinga-Thie GM, Visseren FL. The effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin alone on post-fat load endothelial function in patients with metabolic syndrome: a randomized double-blind crossover trial. J Cardiovasc Pharmacol. 2008 Aug;52(2):145-50.
