Effects of Ezetimibe on Postprandial Hyperlipidemia and Endothelial Function

June 9, 2010 updated by: UMC Utrecht

The Effects of Ezetimibe on Postprandial Hyperlipidemia and Endothelial Dysfunction in Patients With the Metabolic Syndrome.

In the present study the investigators are researching the effects of the cholesterol absorption inhibitor ezetimibe on postprandial lipemia and postprandial endothelial function in patients with the metabolic syndrome. The lipid-lowering effect of high-dose statin monotherapy on fasting lipids is equal to the combination therapy of low-dose statin and ezetimibe.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

In patients at high risk for future cardiovascular events, more intensive LDL cholesterol lowering with high doses statin therapy provides greater protection against death or major cardiovascular events than does a standard regimen. Intensive LDL cholesterol lowering can be achieved by high dose statin treatment or with combination therapy of lower doses statin and ezetimibe. However, it is unclear whether this combination therapy results in the same or more beneficial effects on cardiovascular prognosis.

The metabolic syndrome is a cluster of several vascular risk factors (as abdominal obesity, high blood pressure, hypertriglyceridemia, low HDL cholesterol and high fasting glucose). The underlying pathophysiology is still not fully clarified, but insulin resistance seems to be a main characteristic of this syndrome. Subjects with the metabolic syndrome are at increased risk for the development of cardiovascular morbidity and mortality and type II diabetes. The prevalence of the metabolic syndrome is high in patients with clinical manifestations of vascular diseases and is associated with more vascular damage in these patients.

Insulin resistance is linked to endothelial dysfunction and decreased nitric oxide bioavailability by several mechanisms including, inflammation (as reflected by elevated high sensitive C Reactive Protein (hs-CRP) plasma levels), disruption of insulin receptor signalling cascades, increased production of cytokines and activation of the renin angiotensin system. However, other studies do not support an association between insulin resistance and endothelial function, so this mechanism seems controversial.

In the postprandial state, insulin resistance is associated with hyperlipidemia. Postprandial hyperlipidemia may be an important determinant of endothelial dysfunction as well. Remnants of chylomicron and very low density lipoprotein metabolism impair endothelial dependent vasodilatation. In line with the hypothesis that endothelial function can be used as a surrogate endpoint for cardiovascular morbidity, therapeutic modulation of (postprandial) endothelial function may potentially contribute to prevention of cardiovascular disease in patients with the metabolic syndrome.

Statin therapy modulates (postprandial) endothelial function but it is not known whether this is an indirect effect of lipid-lowering or a direct vascular effect of statins influencing the stability and bioavailability of NOS.

AIMS In the present study we propose to investigate the effects of the cholesterol absorption inhibitor ezetimibe on postprandial lipemia and (postprandial) endothelial function in patients with the metabolic syndrome. High-dose statin monotherapy has the same lipid-lowering effect (on fasting lipids) as the combination therapy of low dose statin and ezetimibe. The latter may reduce postprandial lipemia more effectively and may therefore have beneficial effects on postprandial endothelial dysfunction.

Ezetimibe is unlikely to have a direct vascular effect and therefore any observed change in vascular function is due to a change in postprandial lipemia. As secondary objective of the study, this enables us to differentiate between direct and indirect effects of statin therapy on postprandial endothelial function comparing modulation of postprandial endothelial function by monotherapy simvastatin with combination therapy of simvastatin and ezetimibe.

Hypothesis With comparable reduction in fasting plasma lipids, combination therapy of low-dose statin and ezetimibe reduces postprandial lipemia better than high-dose statin monotherapy. This leads to better postprandial endothelial function in patients with the metabolic syndrome.

Objectives

  1. To determine the effects of combination therapy of low-dose statin and ezetimibe on postprandial hyperlipidemia compared to high-dose statin monotherapy.
  2. To determine the effects of combination therapy of low-dose statin and ezetimibe on postprandial endothelial (dys-)function compared to high-dose statin monotherapy.

Study Type

Interventional

Enrollment

20

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Utrecht, Netherlands, 3584 CX
        • Department of Vascular Medicine UMC Utrecht

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  1. Male and female (postmenopausal) patients, 18-70 years of age

  2. Diagnosis of the metabolic syndrome according to ATP III criteria(4), including 3 or more of the following metabolic abnormalities:

    • abdominal obesity (waist circumference > 102 cm in men and > 88 cm in women)
    • elevated blood pressure (³ 130 mmHg systolic or ³ 85 mmHg diastolic)
    • hypertriglyceridemia (serum triglycerides ³ 1.70 mmol/L
    • low high-density lipoprotein (HDL) cholesterol (serum HDL-cholesterol <1.04 mmol/L in men and < 1.29 mmol/L in women)
    • high fasting glucose (fasting serum glucose ³ 6.1 mmol/L)
  3. Written informed consent

Exclusion Criteria:

  1. Smoking
  2. Thyroid disease (TSH > 5 mU/L with clinical symptoms of hypothyroidism)
  3. Hepatic disease (ASAT or ALAT > 2 times the upper limit of normal)
  4. Renal disease (serum creatinine > 1.7 times the upper limit of normal).
  5. A history of coronary heart disease, cerebrovascular disease or peripheral arterial disease.
  6. Use of lipid lowering therapy
  7. Systolic blood pressure ≥ 180 mmHg and /or diastolic blood pressure ≥ 110 mmHg
  8. BMI > 35
  9. HbA1c > 6.5%
  10. Triglycerides > 8.0 mmol/L

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: DOUBLE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Postprandial lipemia
Time Frame: 0, 1, 2 and 4 hours after eating
0, 1, 2 and 4 hours after eating
Postprandial endothelial function
Time Frame: 0 and 4 hours after the meal
0 and 4 hours after the meal

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

UMC Utrecht

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2004

Study Completion

July 1, 2005

Study Registration Dates

First Submitted

September 12, 2005

First Submitted That Met QC Criteria

September 15, 2005

First Posted (ESTIMATE)

September 16, 2005

Study Record Updates

Last Update Posted (ESTIMATE)

June 10, 2010

Last Update Submitted That Met QC Criteria

June 9, 2010

Last Verified

August 1, 2004

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EZET

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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