Metabolic Syndrome X
Conditions
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.
Interventions
DRUGEzetimibe
Ezetimibe 10 mg/d for 12 weeks
DRUGPlacebo
Placebo for 12 weeks
Sponsors
Laval University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ezetimibe First Then Placebo First intervention: Ezetimibe 10 mg/d for 12 weeks Second intervention: Placebo 12 weeks | 10 |
| Placebo First Then Ezetimibe First intervention: Placebo for 12 weeks Second intervention: Ezetimibe 12 weeks | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Placebo First Then Ezetimibe | Ezetimibe First Then Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 20 Participants |
| Age, Continuous | 39.4 years STANDARD_DEVIATION 13.6 | 39.4 years STANDARD_DEVIATION 7.9 | 39.4 years STANDARD_DEVIATION 10.8 |
| Region of Enrollment Canada | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
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).
Time frame: At the end of the two 12-week interventions (Week 12 and 24)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Change in Intestinal mRNA Expression Levels of LDL Receptor Between the Two 12-week Interventions | 110531 #copies/100000 copies housekeeping gene | Standard Deviation 32604 |
| Placebo | Change in Intestinal mRNA Expression Levels of LDL Receptor Between the Two 12-week Interventions | 95140 #copies/100000 copies housekeeping gene | Standard Deviation 31840 |
Secondary
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).
Time frame: At the end of the two 12-week interventions (Week 12 and 24)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ezetimibe | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | HMGCoA reductase | 354911 #copies/100000 copies housekeeping gene | Standard Deviation 102607 |
| Ezetimibe | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | PCSK9 | 9079 #copies/100000 copies housekeeping gene | Standard Deviation 5816 |
| Ezetimibe | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | SREBP-2 | 193012 #copies/100000 copies housekeeping gene | Standard Deviation 32787 |
| Ezetimibe | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | NPC1L1 | 454298 #copies/100000 copies housekeeping gene | Standard Deviation 97707 |
| Ezetimibe | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | ABCG5 | 271811 #copies/100000 copies housekeeping gene | Standard Deviation 111688 |
| Ezetimibe | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | ABCG8 | 125315 #copies/100000 copies housekeeping gene | Standard Deviation 46842 |
| Placebo | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | ABCG5 | 283863 #copies/100000 copies housekeeping gene | Standard Deviation 132434 |
| Placebo | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | HMGCoA reductase | 311268 #copies/100000 copies housekeeping gene | Standard Deviation 88237 |
| Placebo | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | NPC1L1 | 448686 #copies/100000 copies housekeeping gene | Standard Deviation 138746 |
| Placebo | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | PCSK9 | 8091 #copies/100000 copies housekeeping gene | Standard Deviation 6131 |
| Placebo | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | ABCG8 | 129551 #copies/100000 copies housekeeping gene | Standard Deviation 63246 |
| Placebo | Change in Intestinal mRNA Expression Levels of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA Reductase Between the Two 12-week Interventions | SREBP-2 | 182349 #copies/100000 copies housekeeping gene | Standard Deviation 36681 |
Secondary
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).
Time frame: At the end of the two 12-week interventions (Week 12 and 24)
Population: Data will never be analyzed because the mRNA expression of LDL receptor is sufficient.
Secondary
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).
Time frame: At the end of the two 12-week interventions (Week 12 and 24)
Population: Data will never be analyzed because the mRNA expression of SREBP-2, NPC1L1, ABCG5/8, PCSK9 and HMG CoA reductase are sufficient.