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

Phase 3

Completed

Conditions: Metabolic Syndrome X

Interventions: Drug: Placebo
Drug: Ezetimibe

Registration Number: NCT01849068

Lead Sponsor: Laval University

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 20

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	-
Ezetimibe	Ezetimibe	-

Primary Outcome Measures

Name	Time	Method
Change in Intestinal mRNA Expression Levels of LDL Receptor Between the Two 12-week Interventions	At the end of the two 12-week interventions (Week 12 and 24)	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).

Secondary Outcome Measures

Name	Time	Method
Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions	At the end of the two 12-week interventions (Week 12 and 24)	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).
Change in Intestinal Protein Levels of LDL Receptor Between the Two 12-week Interventions	At the end of the two 12-week interventions (Week 12 and 24)	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).
Change in Protein Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions	At the end of the two 12-week interventions (Week 12 and 24)	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).