Diabetes Mellitus, Postprandial Lipemia
Conditions
Keywords
Diabetes mellitus, Postprandial, Hyperlipidemia, Atherosclerosis
Brief summary
Sitagliptin is a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), and has been shown to reduce fasting and postprandial glucose levels in patients with type 2 diabetes mainly through incretin hormone-mediated improvements in islet function. Although clinical studies to date indicate that fasting lipid levels are minimally affected by DPP-4 inhibitor treatment, animal studies suggested that DPP-4 inhibition reduce intestinal triglyceride (TG) absorption and apolipoprotein production and increased chylomicron catabolism. Therefore, the present study was designed to examine the effects of sitagliptin on postprandial lipemia in patients with type 2 diabetes. A possible reduction in postprandial atherogenic triglyceride-rich lipoproteins (TRL) levels by sitagliptin would add to therapeutic utility of this DPP-4 inhibitor and suggest the potential to reduce cardiovascular risk in patients with type 2 diabetes.
Interventions
DRUGSitagliptin
Sitagliptin 100 mg/d for 6 weeks
DRUGPlacebo
Placebo for 6 weeks
Sponsors
Merck Sharp & Dohme LLC
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 65 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes as defined by the American Diabetes Association; * Non-smoker; * Body mass index between 25.0 and 40.0 kg/m2; * Baseline HbA1c between 6.5 and 8.5%; * Baseline fasting plasma glucose \< 15.0 mmol/L; * Plasma triglyceride levels between 1.5 and 8.0 mmol/L (135 and 710 mg/dl) at week and -4; * Patients having received stable doses of metformin for at least 3 months before randomization; * Subjects must be willing to give written informed consent and able to adhere to dosing schedule, visit schedule and phone follow-up assessment; * Patients should be otherwise generally healthy, without elevations in hepatic transaminases or abnormal renal function or coagulation; * Patients having normal TSH at screening.
Exclusion criteria
* Patients with extreme dyslipidemias, such as familial hypercholesterolemia will be excluded; * Patients with type 1 diabetes, secondary form of diabetes or acute metabolic diabetic complications will be excluded; * Patients having received or being treated with insulin or a thiazolidinedione within the past 6 months will be excluded; * Subjects will be excluded if they have cardiovascular disease (CVD) (coronary heart disease, cerebrovascular disease or peripheral arterial disease) or if they are taking other medications known to affect lipoprotein metabolism (e.g. steroids, beta blockers, thiazide diuretics, lipid lowering agents, significant alcohol intake etc.); * 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; * Individuals with a history of mental instability, drug or alcohol abuse or individuals who have been treated or are being treated for severe psychiatric illness that, in the opinion of the investigator, may interfere with optimal participation in the study; * History of alcohol or drug abuse within the past 2 years. Patients must not take alcohol during the study; * Disorders of the hematologic, digestive, or central nervous systems, including cerebrovascular disease and degenerative disease, that would limit study evaluation or participation; * Known impairment of renal function (serum creatinine levels \> 1.7 mg/dL for men), dysproteinemia, nephrotic syndrome, or other renal disease (24-hour urinary protein ≥3 ± 1 g); * Active or chronic hepatobiliary or hepatic disease. In addition, patients with AST or ALT \>2 x upper limit of the laboratory reference range will be excluded; * Subjects with coagulopathy (prothrombin time \[PT\] or partial thromboplastin time \[PTT\] at Visit 1 \>1.5 times control; * Patients who are known to have tested positive for human immunodeficiency virus (HIV); * Patients who are currently enrolled in another clinical study; * Patients who have used any investigational drug within 30 days of the first clinic visit; * Congestive heart failure NYHA Class III or IV. Uncontrolled cardiac arrhythmias within 3 months of study entry; * Uncontrolled diabetes mellitus (HbA1c\>8.5%) or other endocrine or metabolic disease known to influence serum lipids or lipoproteins. Clinically euthyroid subjects on replacement doses of thyroid hormone are eligible for enrollment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Measurement of the Area Under the Curve of Plasma Triglycerides (TG) Levels During Postprandial Period (Time 0,2,4,6,8 Hours) | At the end of the two 6-week interventions |
Countries
Canada
Participant flow
Recruitment details
Location: CHUL Medical Centre Date: Fall 2007, Winter 2008, Fall 2008
Pre-assignment details
2-weeks run-in period. 6-weeks treatment with sitagliptin 100mg/d or placebo. 4-weeks washout period. 6-weeks treatment with sitagliptin or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Sitagliptin 100 mg/d for 6 weeks | 18 |
| Placebo Placebo for 6 weeks | 18 |
| Total | 36 |
Baseline characteristics
| Characteristic | Placebo | Sitagliptin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 16 Participants | 32 Participants |
| Age Continuous | 58.8 years STANDARD_DEVIATION 6.3 | 57.4 years STANDARD_DEVIATION 6.5 | 58.1 years STANDARD_DEVIATION 6.4 |
| Region of Enrollment Canada | 18 participants | 18 participants | 36 participants |
| Sex: Female, Male Female | 6 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Male | 12 Participants | 18 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 18 | 0 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 |
Outcome results
Primary
Measurement of the Area Under the Curve of Plasma Triglycerides (TG) Levels During Postprandial Period (Time 0,2,4,6,8 Hours)
Time frame: At the end of the two 6-week interventions
Population: We analyzed all the subjects involved in the study. The analysis was per protocol. We compared data from the placebo phase with the sitagliptin phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Measurement of the Area Under the Curve of Plasma Triglycerides (TG) Levels During Postprandial Period (Time 0,2,4,6,8 Hours) | 30.0 mmol*h/L | Standard Deviation 14.5 |
| Sitagliptin 100 mg/d | Measurement of the Area Under the Curve of Plasma Triglycerides (TG) Levels During Postprandial Period (Time 0,2,4,6,8 Hours) | 27.1 mmol*h/L | Standard Deviation 13 |