Effect of Sitagliptin on Incretin Effect in Patients With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the effect of the DPP-4 inhibitor sitagliptin on the incretin effect in patients with type 2 diabetes mellitus.

Detailed Description
-----------------
Following a meal, gut-produced incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the circulation. Because GLP-1 and GIP mediate grossly 60% of the insulin-stimulatory action, the so-called incretin effect, both are crucial components of a natural endogenous system guaranteeing glucose homeostasis. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha-cells and delays nutrient delivery from the stomach by inhibiting gastric emptying. The rise in insulin concentration enhances glucose clearance in peripheral tissues such as muscle, and the lower glucagon concentration combined with the rise in insulin reduces hepatic glucose production. By enhancing glucose clearance and lowering hepatic glucose production, the post-meal glucose excursion is reduced. Both GLP-1 and GIP are degraded by the enzyme dipeptidylpeptidase-4 (DPP-4). Inhibition of DPP-4 by the specific DPP-4 inhibitor Sitagliptin increases plasma levels of both GLP-1 and GIP, and reduces postprandial glycemia. Although important in healthy subjects, the role of the incretin hormones in patients with T2DM is unclear. In T2DM the insulinotropic efficacy of GIP is reduced and the postprandial release of GLP-1 is diminished. Therefore, the aim of this study in T2DM is to quantify the incretin effect with and without the DPP-4 inhibitor sitagliptin. The specific GLP-1 receptor antagonist exendin(9-39) will be used to quantify the contribution of both GLP-1 and GIP to the incretin effect in patients with T2DM.

Official Title
-----------------
A Randomized, Placebo-Controlled, 4-period, Crossover Study to Assess the Impact of MK-0431 (Sitagliptin) on Incretin Effect and the Role of Specific Incretin Hormones in Patients With Type 2 Diabetes Mellitus

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Placebo tablet
* Drug: Sitagliptin tablet
* Drug: Saline infusion
* Drug: Exendin(9-39) infusion


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women with T2DM without childbearing potential Male patients with T2DM using a double-barrier method of contraception must be able to complete a 1 week wash-out of current anti-diabetic medications (patients on PPARγ must be off for at least 4 weeks) no medications which may alter gastric motility (i.e. acetaminophen, erythromycin) except for cardiac medication at a stable dose. Age 30-70 years HbA1c ≤9% at screening BMI<40 kg/m2 Must have a fasting blood glucose of ≤11.1 mmol/L (200 mg/dL) at screening Able to provide written informed consent prior to study participation Able to communicate well with the investigator and comply with the requirements of the study Able to maintain dietetic restrictions and to perform measurements of blood glucose on a daily basis (fasting and two-hours postprandial). Patients must be informed the investigator if fasting glucose is above 200mg/dl or two hours postprandially blood glucose concentration above 240mg/dl is being measured. Exclusion Criteria: T1DM, diabetes as a result of pancreatic injury, or secondary forms of diabetes (eg. Cushing, acromegaly) Females with childbearing potential, breastfeeding and pregnant women Need for insulin within the previous 3 months Use of Thiazolidinediones in the previous 4 weeks Significant concomitant disease or complications of diabetes (i.e. nephropathy, autonomic dysfunction, orthostasis). Fasting triglycerides >5.1 mmol/L (>450 mg/dL) within the past 4 weeks. Treatment with systemic steroids and thyroid hormone (unstable dosage). Patients with any history of gastrointestinal surgery, e.g. partial bowel resections, partial gastric resections, etc. Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing. Significant illness within the two weeks prior to dosing. Past medical history of clinically significant ECG abnormalities or a family history of a prolonged QT-interval syndrome. History of clinically significant drug allergy; history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug or drugs similar to the study drug. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the subject in case of participation in the study. The investigator should be guided by evidence of any of the following: history of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding; history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection; history or clinical evidence of pancreatic injury or pancreatitis; history or presence of impaired renal function as indicated by abnormal creatinine or urea val-ues or abnormal urinary constituents (e.g., albuminuria); evidence of urinary obstruction or difficulty in voiding at screening; Polymorphonuclears <1500/µL at inclusion or platelet count < 100,000/μL at screening and base-line. History of immunocompromise. Evidence of liver disease as indicated by abnormal liver function tests such as SGOT, SGPT, GGT, alkaline phosphatase, or serum bilirubin. SGOT, SGPT, GGT and alkaline phosphatase must not exceed twice the upper limit of the normal range, and serum bilirubin should not exceed the value of 27 µmol/L (1.6 mg/dL). History of drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening evaluations.

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br>placebo PO (placebo control for sitagliptin) for three days. Saline IV (placebo control for exendin(9-39) on two consecutive study days. | Drug: Placebo tablet<br>* placebo PO (placebo control for sitagliptin) for three days<br>Drug: Saline infusion<br>* Saline IV (placebo control for exendin(9-39)) on two consecutive study days<br>|
| Experimental: 2<br>Sitagliptin 100 mg PO for three days. Saline IV (placebo control for exendin(9-39)) on two consecutive study days | Drug: Sitagliptin tablet<br>* Sitagliptin 100 mg PO for three days.<br>Drug: Saline infusion<br>* Saline IV (placebo control for exendin(9-39)) on two consecutive study days<br>|
| Experimental: 3<br>Sitagliptin 100 mg PO for three days. Exendin(9-39) IV on two consecutive study days. | Drug: Sitagliptin tablet<br>* Sitagliptin 100 mg PO for three days.<br>Drug: Exendin(9-39) infusion<br>* Exendin(9-39) IV on two consecutive study days.<br>|
| Placebo Comparator: 4<br>placebo PO (placebo control for sitagliptin) for three days. Exendin(9-39)IV on two consecutive study days. | Drug: Placebo tablet<br>* placebo PO (placebo control for sitagliptin) for three days<br>Drug: Exendin(9-39) infusion<br>* Exendin(9-39) IV on two consecutive study days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To asses the effect of sitagliptin compared to placebo and to coadministration of sitagliptin and the GLP-1 receptor antagonist exendin(9-39)NH2 on the incretin effect after an oral glucose challenge. |  | during 240 minutes after ingestion of an OGTT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma glucagon, plasma GIP, plasma GLP-1, Insulin, C-peptide, plasma glucose profiles. 13CO2 exhalation kinetics assessing gastric emptying |  | during 240 minutes after ingestion of an OGTT | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
diabetes mellitus, DPP-4 inhibitor, sitagliptin, exendin(9-39), GLP-1