Type 2 Diabetes Mellitus
Conditions
Keywords
sitagliptin, diabetes, apolipoprotein B48 and B100
Brief summary
Sitagliptin is a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-IV), 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 \[13\]. Although clinical studies to date indicate that fasting lipid levels are minimally affected by DPP-IV inhibitor treatment \[14-16\], animal studies suggested that DPP-IV inhibition reduce intestinal triglycerides (TG) absorption and apolipoprotein (apo) production \[17\] and increased chylomicron catabolism \[18\]. Interestingly, a recent study supporting this hypothesis showed that vildagliptin therapy was able to reduce postprandial intestinal triglyceride-rich lipoproteins (TRL) particles in patients with type 2 diabetes \[19\]. Recently, our group has reported that sitagliptin treatment significantly reduced plasma apo B-48 and TG concentrations in the postprandial state. Moreover, animal studies showed that sitagliptin decreased intestinal secretion of intestinal apo B-48, mainly by increasing level of glucagon-like peptide (GLP)-1 \[20\]. Therefore, the present study was designed to examine the effects of sitagliptin on the kinetics of TRL apo B-48 and in patients with type 2 diabetes. A possible reduction in postprandial atherogenic TRL apo B-48-containing lipoprotein 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
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males 18 to 65 years of age. * Post-menopausal women under age 65 on stable medical therapy for 6 months before the study (the patient should have demonstrated stable lipid panels) * Women should not be on hormone replacement therapy (no recent starting or stopping) * Type 2 diabetes as defined by the American Diabetes Association. * Non-smoker. * Body mass index between 25.0 and 40.0 kg/m2. * Baseline glycated hemoglobin A1c (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 screening and week -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 thyroid stimulating hormone 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. * Patients taking any other hypoglycemic agent, other than metformin. * Subjects will be excluded if they have cardiovascular disease (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 aspartate aminotransferase or alanine aminotransferase \>2 x upper limit of the laboratory reference range will be excluded. * Subjects with coagulopathy (prothrombin time or partial thromboplastin time at Visit 1 \>1.5 times control). * Subjects with hemoglobin \>2 x the lower limit of the laboratory reference range will be excluded. * 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 New York Heart Association (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 Apolipoprotein B48 and Apolipoprotein B100 Production Rates With Stable Isotope During Postprandial Period | 6 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Measurement of Glucagon-like Peptide-1 by ELISA | 6 weeks |
| Measurement of Glucose | 6 weeks |
| Measurement of Insulin | 6 weeks |
| Measurement of Apolipoprotein B48 and Apolipoprotein B100 Pool Sizes With Stable Isotope During Postprandial Period | 6 weeks |
| Measurement of Apolipoprotein B48 and Apolipoprotein B100 Fractional Catabolic Rates With Stable Isotope During Postprandial Period | 6 weeks |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin First Then Placebo First intervention: Sitagliptin 100 mg/d for 6 weeks Washout: 4 weeks Second intervention: Pacebo for 6 weeks | 11 |
| Placebo First Then Sitagliptin First intervention: Placebo for 6 weeks Washout: 4 weeks Second intervention: Sitagliptin 100 mg/d for 6 weeks | 11 |
| Total | 22 |
Baseline characteristics
| Characteristic | Sitagliptin First Then Placebo | Total | Placebo First Then Sitagliptin |
|---|---|---|---|
| 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 | 11 Participants | 22 Participants | 11 Participants |
| Age, Continuous | 57.5 years STANDARD_DEVIATION 4.6 | 58.2 years STANDARD_DEVIATION 3.8 | 59 years STANDARD_DEVIATION 2.9 |
| Region of Enrollment Canada | 11 participants | 22 participants | 11 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 9 Participants | 18 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 22 | 0 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 |
Outcome results
Primary
Measurement of Apolipoprotein B48 and Apolipoprotein B100 Production Rates With Stable Isotope During Postprandial Period
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sitagliptin | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Production Rates With Stable Isotope During Postprandial Period | apolipoprotein B48 production rate | 2.1 mg/kg/day | Standard Deviation 0.7 |
| Sitagliptin | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Production Rates With Stable Isotope During Postprandial Period | apolipoprotein B100 production rate | 27.5 mg/kg/day | Standard Deviation 8.4 |
| Placebo | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Production Rates With Stable Isotope During Postprandial Period | apolipoprotein B48 production rate | 2.5 mg/kg/day | Standard Deviation 1.2 |
| Placebo | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Production Rates With Stable Isotope During Postprandial Period | apolipoprotein B100 production rate | 30.3 mg/kg/day | Standard Deviation 11.3 |
Secondary
Measurement of Apolipoprotein B48 and Apolipoprotein B100 Fractional Catabolic Rates With Stable Isotope During Postprandial Period
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sitagliptin | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Fractional Catabolic Rates With Stable Isotope During Postprandial Period | apolipoprotein B48 fractional catabolic rate | 6.2 pools/day | Standard Deviation 2.5 |
| Sitagliptin | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Fractional Catabolic Rates With Stable Isotope During Postprandial Period | apolipoprotein B100 fractional catabolic rate | 5.9 pools/day | Standard Deviation 2.3 |
| Placebo | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Fractional Catabolic Rates With Stable Isotope During Postprandial Period | apolipoprotein B48 fractional catabolic rate | 6.3 pools/day | Standard Deviation 3.2 |
| Placebo | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Fractional Catabolic Rates With Stable Isotope During Postprandial Period | apolipoprotein B100 fractional catabolic rate | 5.9 pools/day | Standard Deviation 2.6 |
Secondary
Measurement of Apolipoprotein B48 and Apolipoprotein B100 Pool Sizes With Stable Isotope During Postprandial Period
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sitagliptin | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Pool Sizes With Stable Isotope During Postprandial Period | apolipoprotein B48 pool size | 38.4 mg | Standard Deviation 25.8 |
| Sitagliptin | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Pool Sizes With Stable Isotope During Postprandial Period | apolipoprotein B100 pool size | 488.0 mg | Standard Deviation 210.2 |
| Placebo | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Pool Sizes With Stable Isotope During Postprandial Period | apolipoprotein B48 pool size | 48.5 mg | Standard Deviation 45.2 |
| Placebo | Measurement of Apolipoprotein B48 and Apolipoprotein B100 Pool Sizes With Stable Isotope During Postprandial Period | apolipoprotein B100 pool size | 537.8 mg | Standard Deviation 232 |
Secondary
Measurement of Glucagon-like Peptide-1 by ELISA
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Measurement of Glucagon-like Peptide-1 by ELISA | 5.6 pmol/L | Standard Deviation 6.8 |
| Placebo | Measurement of Glucagon-like Peptide-1 by ELISA | 3.1 pmol/L | Standard Deviation 5.8 |
Secondary
Measurement of Glucose
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Measurement of Glucose | 7.7 mmol/L | Standard Deviation 1.2 |
| Placebo | Measurement of Glucose | 8.9 mmol/L | Standard Deviation 1.5 |
Secondary
Measurement of Insulin
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Measurement of Insulin | 161.1 pmol/L | Standard Deviation 91.7 |
| Placebo | Measurement of Insulin | 179.5 pmol/L | Standard Deviation 88.1 |