Sitagliptin and Kinetics of Triglyceride-rich Lipoproteins Apolipoprotein B48 and B100 in Patients With Type 2 Diabetes

Type 2 Diabetes Mellitus Clinical Trial

— JANUB48  

Official title:

A Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the Effects of Sitagliptin on the Kinetics of Triglyceride-rich Lipoproteins Apolipoprotein B48 and Apolipoprotein B100 in Patients With Type 2 Diabetes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01334229
• Other study ID #: IIS#39262
• Status: Completed
• Phase: Phase 3
• First received: April 11, 2011
• Last updated: September 3, 2014
• Start date: April 2011
• Est. completion date: December 2013

Study information

• Verified date: September 2014
• Source: Laval University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: December 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Sitagliptin
Sitagliptin 100 mg/d for 6 weeks
• Placebo
Placebo for 6 weeks

Locations

Country	Name	City	State
Canada	Laval University	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
Laval University	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measurement of Apolipoprotein B48 and Apolipoprotein B100 Production Rates With Stable Isotope During Postprandial Period		6 weeks	No
Secondary	Measurement of Glucagon-like Peptide-1 by ELISA		6 weeks	No
Secondary	Measurement of Glucose		6 weeks	No
Secondary	Measurement of Insulin		6 weeks	No
Secondary	Measurement of Apolipoprotein B48 and Apolipoprotein B100 Pool Sizes With Stable Isotope During Postprandial Period		6 weeks	No
Secondary	Measurement of Apolipoprotein B48 and Apolipoprotein B100 Fractional Catabolic Rates With Stable Isotope During Postprandial Period		6 weeks	No