Hyperlipidemia
Conditions
Keywords
Intestinal lipoprotein, Apolipoprotein B48 and apolipoprotein B100, Pancreatic clamp, DPPIV inhibitor
Brief summary
Recent studies in both animals and humans has demonstrated that the hormone GLP-1 (glucagon like peptide 1) reduces intestinal production of lipoprotein particles. The investigators therefore hypothesise that the drug sitagliptin which prevents the breakdown of GLP-1 will reduce intestinal lipoprotein production in humans. The investigators are unable to speculate whether sitagliptin will affect hepatic lipoprotein production because of lack of of data from animal studies or in vitro data. Sitagliptin is already an approved treatment for type 2 diabetes.
Detailed description
Each subject will be studied twice 4-6 weeks apart in random order in this single blinded study. In study A they will receive a single dose of sitagliptin 100mg od. In study B they will receive placebo. A nasoduodenal tube will be sited under fluoroscopic guidance the day prior to the study. On the day of the study regular liquid formula (Great shake plus) will be infused from 4am through the tube to maintain a constant fed state. A pancreatic clamp (octreotide with replacement glucose, insulin and growth hormone) along with saline/sitagliptin will be started at 7am. From 9am an iv bolus of deuterated-glycerol (d5-glycerol) along with a regular infusion of deuterated leucine (L-\[5,5,5-2H3\]. Regular blood samples will be drawn to assess lipoprotein kinetics.
Interventions
DRUGSitagliptin
Sitagliptin, 100mg, oral, single dose
DRUGPlacebo
Placebo, oral, single dose
Sponsors
Merck Frosst Canada Ltd.
University Health Network, Toronto
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Men and women, aged 18 to 60 years 2. Body mass index 20 kg/m2 to 27 kg/m2 3. Hemoglobin above 130g/L. 4. Normal glucose tolerance in response to a 75g, 2-hr OGTT
Exclusion criteria
1. Subject has a history of hepatitis/hepatic disease that has been active within the previous two years. 2. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (Cr \> 1.5 mg/dL), genitourinary, hematological systems, or has severe uncontrolled treated or untreated hypertension (sitting diastolic BP \> 100 or systolic \> 180) or proliferative retinopathy 3. History of diabetes or OGTT indicative of diabetes or impaired glucose tolerance. 4. Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or decompensated heart failure. 5. Any laboratory values: AST \> 2x ULN; ALT \> 2x ULN TSH \> 6 mU/l 6. Current addiction to alcohol or substances of abuse as determined by the investigator. 7. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation 8. Taking any prescription or non-prescription medications at the time of the study 9. Having donated blood three months prior to and three months post study procedures 10. A pregnancy test will be performed 1 to 3 days prior to each study in all female subjects. Those who test positive for pregnancy will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apolipoprotein B48 Production Rate After Acute Oral Administration of 100mg Sitagliptin (Compared to Placebo) | 10 hours | Apolipoprotein B48 turnover was measured in a 10-hour kinetic study with in vivo tracer techniques and mathematical modeling to calculate production rates. Studies were performed under conditions of a pancreatic clamp and a steady state fed state in volunteers receiving single oral dose of either 100mg sitagliptin or matching placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apolipoprotein B100 Production Rate After Acute Oral Administration of 100mg Sitagliptin (Compared to Placebo) | 10 hours | Apolipoprotein B100 turnover was measured in a 10-hour kinetic study with in vivo tracer techniques and mathematical modeling to calculate production rates. Studies were performed under conditions of a pancreatic clamp and a steady state fed state in volunteers receiving single oral dose of either 100mg sitagliptin or matching placebo. |
Countries
Canada
Participant flow
Recruitment details
Local newspaper advertisement
Pre-assignment details
21 participants were enrolled in the study, however only 15 were started.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants placebo, oral, single dose sitagliptin, 100 mg, oral, single dose | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 42.3 years STANDARD_DEVIATION 2.6 |
| Body mass index | 24.6 kg/m^2 STANDARD_DEVIATION 0.6 |
| Glucose Levels | 4.9 mmol/l STANDARD_DEVIATION 0.1 |
| Region of Enrollment Canada | 15 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 15 Participants |
| Triglyceride Levels | 1.2 mmol/l STANDARD_DEVIATION 0.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
Apolipoprotein B48 Production Rate After Acute Oral Administration of 100mg Sitagliptin (Compared to Placebo)
Apolipoprotein B48 turnover was measured in a 10-hour kinetic study with in vivo tracer techniques and mathematical modeling to calculate production rates. Studies were performed under conditions of a pancreatic clamp and a steady state fed state in volunteers receiving single oral dose of either 100mg sitagliptin or matching placebo.
Time frame: 10 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Apolipoprotein B48 Production Rate After Acute Oral Administration of 100mg Sitagliptin (Compared to Placebo) | 122.9 ug/kg/day | Standard Error 30.4 |
| Sitagliptin | Apolipoprotein B48 Production Rate After Acute Oral Administration of 100mg Sitagliptin (Compared to Placebo) | 60.6 ug/kg/day | Standard Error 12.2 |
Secondary
Apolipoprotein B100 Production Rate After Acute Oral Administration of 100mg Sitagliptin (Compared to Placebo)
Apolipoprotein B100 turnover was measured in a 10-hour kinetic study with in vivo tracer techniques and mathematical modeling to calculate production rates. Studies were performed under conditions of a pancreatic clamp and a steady state fed state in volunteers receiving single oral dose of either 100mg sitagliptin or matching placebo.
Time frame: 10 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Apolipoprotein B100 Production Rate After Acute Oral Administration of 100mg Sitagliptin (Compared to Placebo) | 17.6 mg/kg/day | Standard Error 1.8 |
| Sitagliptin | Apolipoprotein B100 Production Rate After Acute Oral Administration of 100mg Sitagliptin (Compared to Placebo) | 20.4 mg/kg/day | Standard Error 2.9 |