Effects of Selective Inhibition of Cholesterol Absorption With Ezetimibe on Intestinal Cholesterol Homeostasis in Dyslipidemic Men With Insulin-resistance - a Pilot Study
Condition: Metabolic Syndrome X
MeSH terms: Metabolic Syndrome; Insulin Resistance
Intervention: Ezetimibe; Placebo
Intervention description: Ezetimibe 10 mg/d for 12 weeks; Placebo for 12 weeks
Intervention MeSH terms: Ezetimibe
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 20.0
Sex: Male
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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.