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

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ClinicalTrials.gov Identifier: NCT00411411
Recruitment Status : Completed
First Posted : December 14, 2006
Results First Posted : August 13, 2014
Last Update Posted : August 13, 2014
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Kasper Aaboe, University Hospital, Gentofte, Copenhagen

Study Description
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Brief Summary:

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 or disease Intervention/treatment Phase
Type 2 Diabetes Drug: Januvia Drug: Placebo Phase 3

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 49 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, 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
Study Start Date : February 2007
Actual Primary Completion Date : February 2009
Actual Study Completion Date : March 2009

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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


Outcome Measures
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Primary Outcome Measures :
  1. the Relative Increase in Meal-induced Total GLP-1 Secretion [ Time Frame: 12 weeks ]
    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).

  2. Restoration of the Insulinotropic Effect of GIP [ Time Frame: 12 weeks ]
    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 :
  1. Examination of GLP-2, Somatostatin, Glucagon, Peptide-YY and Two Glycaemic Control Parameters (HbA1c and Fasting Plasma Glucose) [ Time Frame: 12 weeks ]
    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


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00411411


Locations
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Denmark
Gentofte Hospital
Hellerup, Denmark, 2900
Sponsors and Collaborators
University Hospital, Gentofte, Copenhagen
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Kasper Aaboe, MD Gentofte University Hospital
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Kasper Aaboe, Doctor, University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier: NCT00411411    
Other Study ID Numbers: 1502
First Posted: December 14, 2006    Key Record Dates
Results First Posted: August 13, 2014
Last Update Posted: August 13, 2014
Last Verified: July 2014
Keywords provided by Kasper Aaboe, University Hospital, Gentofte, Copenhagen:
GLP-1
GIP
Incretin hormones
 DPP-IV inhibitor
Hyperglycaemic clamp
Meal test
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sitagliptin Phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
 Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action