Long Term Effects of DPP-IV Inhibitor Treatment in Patients With Type 2 Diabetes

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Kasper Aaboe, University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier:
NCT00411411
First received: December 13, 2006
Last updated: July 21, 2014
Last verified: July 2014
  Purpose

We wish to evaluate the effect of long term treatment with a DPP-IV inhibitor on the function of the incretin hormones

Hypothesis We hypothesize that that a gradual improvement in metabolic control induced by DPP-IV inhibitor (Januvia®) treatment significantly ameliorates the impaired secretion and potency of GLP-1 and leads to a restoration of the lost action of GIP.


Condition Intervention Phase
Type 2 Diabetes
Drug: Januvia
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Phase 3, Double Blinded, Placebo Controlled Study of the Effects of 12 Weeks DPP-IV Inhibitor Treatment on Secretion and Action of the Incretin Hormones in Patients With Type 2 Diabetes

Resource links provided by NLM:


Further study details as provided by University Hospital, Gentofte, Copenhagen:

Primary Outcome Measures:
  • the Relative Increase in Meal-induced Total GLP-1 Secretion [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Patients will be followed for 12 weeks with three meal test examinations; before treatment, after 1 week of treatment and after 12 weeks of treatment. Primary outcome is AUC GLP-1 (pM x 120 as stated).

  • Restoration of the Insulinotropic Effect of GIP [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Restoration of the insulinotropic effect of GIP measured as the relative increase in GIP induced amplification of the late phase insulin secretion (AUC) response to glucose. Patients will be followed for 12 weeks with examinations after 1 and after 12 weeks of treatment.


Secondary Outcome Measures:
  • Examination of GLP-2, Somatostatin, Glucagon, Peptide-YY and Two Glycaemic Control Parameters (HbA1c and Fasting Plasma Glucose) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Secondary objectives are examination of GLP-2, somatostatin, glucagon, peptide-YY and two glycaemic control parameters (HbA1c and fasting plasma glucose). Patients will be followed for 12 weeks with three examinations; before, during and after the treatment


Enrollment: 49
Study Start Date: February 2007
Study Completion Date: March 2009
Primary Completion Date: February 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Placebo treatment, administered as tablets.
Drug: Placebo
Placebo
Experimental: Januvia
Active treatment
Drug: Januvia
200 mg t.i.d
Other Name: Sitagliptin

Detailed Description:

Background The incretin effect, primarily mediated by the peptide hormones GIP and GLP-1, is known to be impaired in patients with type 2 diabetes, and characterised by reduced GLP-1 secretion and potency and a lack of responsiveness to the insulinotropic effect of GIP. The cause of this defect remains unknown, but exogenous administration of GLP-1 has shown promising results in attempts to restore the incretin effect. Due to rapid degradation of both incretin hormones by the enzyme dipeptidyl-peptidase IV (DPP-IV), treatment strategies now focus on GLP-1 analogues and prevention of hormone degradation through DPP-IV inhibition.

Hypothesis We hypothesize that that a gradual improvement in metabolic control induced by DPP-IV inhibitor (Januvia®) treatment significantly ameliorates the impaired secretion and potency of GLP-1 and leads to a restoration of the lost action of GIP.

Objective To assess the effect of three months treatment with Januvia®, administered as tablets once daily, on metabolic control in metformin treated patients with type 2 diabetes, measured as increases in incretin hormones and insulin secretion.

Efficacy end points Primary efficacy end point in trial part one is the relative increase in meal-induced total GLP-1 secretion after one and twelve weeks of Januvia® treatment.

Primary efficacy end point in part two is restoration of the insulinotropic effect of GIP, measured as the relative increase in GIP induced amplification of the late phase insulin secretion (AUC) response to glucose after 12 weeks of Januvia® treatment.

Secondary objectives are examination of GLP-2, somatostatin, glucagon, peptide-YY and two glycaemic control parameters (HbA1c and fasting plasma glucose)

Design This is a single centre, randomized, double blinded, placebo controlled trial. The trial consists of two parts, each consisting of three months of inhibitor treatment. In each part, 24 patients, recruited from the Diabetes Outpatient Clinic of Gentofte University Hospital, will be randomized to a treatment supplement of either Januvia® or placebo.

Procedures During the trial, patients will be tested with well established procedures. In part one, patients will undergo a standardized meal test and two β-cell secretory capacity tests. In part two, patients will undergo standardized hyperglycaemic GIP, GLP-1 and saline clamps.

Safety The trial has a short time span of only three months. With more than ten visits during this time and regular blood sampling, the patients are well monitored.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  • Type 2 diabetes diagnosed according to and in accordance with the WHO criteria
  • Metformin treatment of ≥ 1 gram
  • 7,5 % ≤ HbA1c ≤ 10%
  • Age > 18
  • BMI ≥ 25 kg/m2
  • Informed consent
  • Contraception, if appropriate

Exclusion criteria

  • Proliferating retinopathy
  • Uremia, end stage renal disease, diabetic nephropathy or any other cause of impaired renal function with s-creatinine > 130 µM and/or albuminuria (>300 mg/day)
  • Liver disease with ALAT and/or ASAT > 2 x normal value
  • Complicated coronary artery disease, NYHA group III and IV
  • Positive screening for islet cell auto antibodies and/or GAD-65 auto antibodies
  • Occurrence of type 1 diabetes in first degree relatives
  • Anaemia
  • Pregnancy and/or breast feeding
  • Treatment with medication affecting insulin secretion
  • non-compliance

Withdrawal criteria

  • The subject may withdraw at will at any time
  • Pregnancy discovered during the trial
  • Severe illness
  • Unacceptable side effects
  • If self-measured fasting plasma glucose on three consecutive days exceeds 15 mM, the result is repeated in an immediately scheduled visit, and no treatable intercurrent cause for the hyperglycaemia can be found.
  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: NCT00411411

Locations
Denmark
Gentofte Hospital
Hellerup, Denmark, 2900
Sponsors and Collaborators
University Hospital, Gentofte, Copenhagen
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Kasper Aaboe, MD Gentofte University Hospital
  More Information

No publications provided

Responsible Party: Kasper Aaboe, Doctor, University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier: NCT00411411     History of Changes
Other Study ID Numbers: 1502
Study First Received: December 13, 2006
Results First Received: May 19, 2014
Last Updated: July 21, 2014
Health Authority: Denmark: Danish Medicines Agency

Keywords provided by University Hospital, Gentofte, Copenhagen:
GLP-1
GIP
Incretin hormones
DPP-IV inhibitor
Hyperglycaemic clamp
Meal test

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

ClinicalTrials.gov processed this record on August 28, 2014