Effects of Selective Inhibition of Cholesterol Absorption With Ezetimibe on Intestinal Cholesterol Homeostasis in Dyslipidemic Men With Insulin-resistance - a Pilot Study

Study Overview
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Brief Summary
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Ezetimibe has been shown to inhibit cholesterol absorption and several lines of evidence from in vitro systems and animal models suggest that this effect is associated with an increase in low-density lipoprotein (LDL) receptor expression in the small intestine. The impact of a treatment with ezetimibe on intestinal gene expression and protein mass levels of LDL receptor and other key genes involved in intestinal cholesterol homeostasis will be examined in dyslipidemic men with insulin-resistance. In the present study, gene expression studies and protein mass levels will be assessed on duodenal biopsies by real-time polymerase chain reaction (rt-PCR) and liquid chromatography-mass spectrometry (LC-MS/MS), respectively. The primary objective of this proposal is to examine the effects of ezetimibe on intestinal gene expression (rt-PCR) and protein mass levels (LC-MS/MS) of LDL receptor in dyslipidemic men with insulin-resistance. The secondary objective is to examine the impact of ezetimibe treatment on intestinal gene expression and protein mass levels of sterol regulatory element-binding protein (SREBP)-2, Niemann-Pick C1-Like1 (NPC1L1), ATP binding cassette gene (ABCG)-5/8, proprotein convertase subtilisin/kexin type 9 (PCSK9) and 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase. Primary hypothesis Treatment with ezetimibe 10 mg/day will significantly increase duodenal mRNA and protein mass levels of LDL receptor in dyslipidemic men with insulin-resistance. Secondary hypothesis Treatment with ezetimibe 10 mg/day will significantly increase duodenal mRNA and protein mass levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA reductase in dyslipidemic men with insulin-resistance.

Official Title
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Effects of Selective Inhibition of Cholesterol Absorption With Ezetimibe on Intestinal Cholesterol Homeostasis in Dyslipidemic Men With Insulin-resistance - a Pilot Study

Conditions
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Metabolic Syndrome X

Intervention / Treatment
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* Drug: Ezetimibe
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men aged between 18-60 years Waist circumference > 102 cm HDL-cholesterol < 1.1 mmol/L Triglycerides > 1.7 mmol/L Fasting blood glucose > 6.1 mmol/L Normal blood pressure (<130/85) Exclusion Criteria: Women Men < 18 or > 60 years Smokers (> 1 cigarette/day) Body weight variation > 10% during the last 6 months prior to the study baseline Subjects with a previous history of cardiovascular disease Subjects with type 2 diabetes Subjects with a monogenic dyslipidemia Subjects on hypertension medications or medications known to affect lipoprotein metabolism or the integrity of gastrointestinal mucosa Subjects with endocrine or gastrointestinal disorders History of alcohol or drug abuse within the past 2 years Subjects who are in a situation or have any condition that, in the opinion of the investigator, may interfere with optimal participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ezetimibe<br> | Drug: Ezetimibe<br>* Ezetimibe 10 mg/d for 12 weeks<br>* Other names: Ezetrol;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Intestinal mRNA Expression Levels of LDL Receptor Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | At the end of the two 12-week interventions (Week 12 and 24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | At the end of the two 12-week interventions (Week 12 and 24) | 
| Change in Intestinal Protein Levels of LDL Receptor Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | At the end of the two 12-week interventions (Week 12 and 24) | 
| Change in Protein Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | We combined the results at the end of each ezetimibe phase from both sequence (average and standard deviation). We combined the results at the end of each placebo phase from both sequence (average and standard deviation). | At the end of the two 12-week interventions (Week 12 and 24) |