Sitagliptin and Kinetics of Triglyceride-rich Lipoproteins Apolipoprotein B48 and B100 in Patients With Type 2 Diabetes
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Sitagliptin; Placebo
Intervention description: Sitagliptin 100 mg/d for 6 weeks; Placebo for 6 weeks
Intervention MeSH terms: Sitagliptin Phosphate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: sitagliptin; diabetes; apolipoprotein B48 and B100

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.
    

Eligibility criteria:

        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.