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

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Joerg Schirra, Ludwig-Maximilians - University of Munich
ClinicalTrials.gov Identifier:
NCT00551590
First received: October 30, 2007
Last updated: October 3, 2011
Last verified: October 2011
  Purpose

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.


Condition Intervention Phase
Type 2 Diabetes Mellitus
Drug: Placebo tablet
Drug: Sitagliptin tablet
Drug: Saline infusion
Drug: Exendin(9-39) infusion
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Diagnostic
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

Resource links provided by NLM:


Further study details as provided by Ludwig-Maximilians - University of Munich:

Primary Outcome Measures:
  • 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. [ Time Frame: during 240 minutes after ingestion of an OGTT ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Plasma glucagon, plasma GIP, plasma GLP-1, Insulin, C-peptide, plasma glucose profiles. 13CO2 exhalation kinetics assessing gastric emptying [ Time Frame: during 240 minutes after ingestion of an OGTT ] [ Designated as safety issue: No ]

Enrollment: 24
Study Start Date: December 2007
Study Completion Date: September 2011
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: 1
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
placebo PO (placebo control for sitagliptin) for three days
Drug: Saline infusion
Saline IV (placebo control for exendin(9-39)) on two consecutive study days
Experimental: 2
Sitagliptin 100 mg PO for three days. Saline IV (placebo control for exendin(9-39)) on two consecutive study days
Drug: Sitagliptin tablet
Sitagliptin 100 mg PO for three days.
Drug: Saline infusion
Saline IV (placebo control for exendin(9-39)) on two consecutive study days
Experimental: 3
Sitagliptin 100 mg PO for three days. Exendin(9-39) IV on two consecutive study days.
Drug: Sitagliptin tablet
Sitagliptin 100 mg PO for three days.
Drug: Exendin(9-39) infusion
Exendin(9-39) IV on two consecutive study days.
Placebo Comparator: 4
placebo PO (placebo control for sitagliptin) for three days. Exendin(9-39)IV on two consecutive study days.
Drug: Placebo tablet
placebo PO (placebo control for sitagliptin) for three days
Drug: Exendin(9-39) infusion
Exendin(9-39) IV on two consecutive study days.

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.

  Eligibility

Ages Eligible for Study:   30 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00551590

Locations
Germany
Clinical Research unit, Dept. of Internal Medicine II - Großhadern, University of Munich
Munich, Germany, 81377
Sponsors and Collaborators
Ludwig-Maximilians - University of Munich
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Joerg Schirra, MD Clinical Research Unit, Dept. of Internal Medicine II, University of Munich
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Joerg Schirra, Prof. Dr. med., Ludwig-Maximilians - University of Munich
ClinicalTrials.gov Identifier: NCT00551590     History of Changes
Other Study ID Numbers: SITEX-02, EudraCT 2007-001050-83
Study First Received: October 30, 2007
Last Updated: October 3, 2011
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Ludwig-Maximilians - University of Munich:
diabetes mellitus
DPP-4 inhibitor
sitagliptin
exendin(9-39)
GLP-1

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Incretins
Sitagliptin
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Hypoglycemic Agents
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 21, 2014