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Pharmacokinetics Study of Dipeptidyl Peptidase 4 Inhibitor to Control Type 2 Diabetes Mellitus

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01449747
First Posted: October 10, 2011
Last Update Posted: December 14, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ji Hyun Kim, The Catholic University of Korea
  Purpose
The purpose of this study is to confirm the mechanism of reduced response to DPP-4 inhibitor in some patients with type 2 diabetes and evaluate appropriate patients to treat with DPP-4 inhibitor

Condition Intervention Phase
Type 2 Diabetes Mellitus Drug: Sitagliptin Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Mechanism of Reduced Response to DPP-4 Inhibitor in Patients With Type 2 Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Ji Hyun Kim, The Catholic University of Korea:

Primary Outcome Measures:
  • Plasma Concentration of Active Glucagon-like Peptide 1 (GLP-1) Before and After Sitagliptin Treatment [ Time Frame: 0, 15, 30, 45, 60, 90, 120, 180 min pre and post-dose ]
    Plasma concentrations of active GLP-1 were measured at 0, 15, 30, 45, 60, 90, 120 and 180 min during the meal tolerance test (MTT). Second measurement of active GLP-1 were measured with MTT after taking sitagliptin 100 mg 1 hour before the test.

  • Plasma Concentration of Total GLP-1 Before and After Sitagliptin Treatment [ Time Frame: 0, 15, 30, 45, 60, 90, 120, 180 min pre and post-dose ]
    Plasma concentrations of total GLP-1 were measured at 0, 15, 30, 45, 60, 90, 120 and 180 min during the meal tolerance test. Second measurement of total GLP-1 were measured with MTT after taking sitagliptin 100 mg 1 hour before the test.

  • Plasma Concentration of Total Glucose-dependent Insulinotropic Polypeptide (GIP) Before and After Sitagliptin Treatment [ Time Frame: 0, 15, 30, 45, 60, 90, 120, 180 min pre and post-dose ]
    Plasma concentrations of total GIP were measured at 0, 15, 30, 45, 60, 90, 120 and 180 min during the meal tolerance test. Second measurement of total GIP were measured with MTT after taking sitagliptin 100 mg 1 hour before the test.

  • Change in AUC of Active GLP-1, Total GLP-1 and Total GIP Between Before and After Sitagliptin Treatment [ Time Frame: 0, 15, 30, 45, 60, 90, 120, 180 min pre and post-dose ]
    Plasma concentrations of active GLP-1, total GLP-1 and total GIP were measured at 0, 15, 30, 45, 60, 90, 120 and 180 min during the meal tolerance test. Second measurements were measured with MTT after taking sitagliptin 100 mg 1 hour before the test. Comparisons were made using Area under the curve (AUC) values and incremental area under the curve (ΔAUC) of active GLP-1, total GLP-1 and total GIP before and after the addition of sitagliptin.


Secondary Outcome Measures:
  • Differences of DPP-4 Activity After Sitagliptin Treatment Between Responder and Non-responder Groups [ Time Frame: 0, 15, 30, 45, 60 min post-dose ]
    The DPP-4 activity was measured at baseline and 0, 15, 30, 45 and 60 min during the meal tolerance test. Second measurement of DPP-4 activity was measured with MTT after taking sitagliptin 100 mg 1 hour before the test. Plasma DPP-4 activity during meal tolerance test is expressed as percentage activity relative to baseline. DPP-4 activity % was calculated using the following formula : (DPP-4 activity at time t / Baseline DPP-4 activity) × 100.


Enrollment: 24
Study Start Date: December 2011
Study Completion Date: July 2015
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: study group
sitagliptin hypo-response patients
Drug: Sitagliptin
Sitagliptin (100mg, per oral) once a day.
Other Name: Januvia
Sham Comparator: control group
sitagliptin response patients
Drug: Sitagliptin
Sitagliptin (100mg, per oral) once a day.
Other Name: Januvia

Detailed Description:

Sitagliptin, a DPP-4 inhibitor was used as an incretin enhancer in clinical practice first. In clinical trials, sitagliptin showed effective control of blood glucose level in type 2 diabetes and 100 mg once daily with metformin was similar to sulfonylurea (glipizide) with metformin in lowering HbA1c. Mostly in practice, stable blood glucose levels were maintained after change of sulfonylurea to sitagliptin in type 2 diabetes treatment. However, in some cases, there were abrupt severe hyperglycemia and uncontrolled blood glucose level after drug change to sitagliptin.

Several mechanism could be considered for reduced response to DPP-4 inhibitor in some type 2 diabetes patients. Firstly, significantly reduced secretion of glucagon-like peptide 1 (GLP-1) more than expected in diabetes or functional defect of GLP-1 activity could be the mechanism of loss of GLP-1 effect irrespective of DPP-4. Secondly, mutation or functional defect of DPP-4 enzyme could not be inhibited by DPP-4 inhibitor. Thirdly, GLP-1 receptor mutation or other defect in β-cell responsiveness to GLP-1 leads to reduction of response to DPP-4 inhibitor.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetic patients with less than 15 yrs of disease duration
  • BMI between 22-27 kg/m2
  • HbA1c ≤ 9% at recruitment

    1. Study group

After change sulfonylurea to sitagliptin in case of metformin and sulfonylurea therapy

  1. Increase of fasting blood glucose over 20 mg/dL or postprandial glucose over 30 mg/dL within several days or
  2. Increase of HbA1c over 1% within 2-3 months without abrupt increase of blood glucose levels within several days

    • Sulfonylurea dose : less than glimepiride 4mg or gliclazide 120mg or glibenclamide 10mg
    • Metformin dose : 500~2000mg
  3. Reduced response to sitagliptin should be made a decision by investigators after understanding the condition of patients surely.

2. Control group

  • Age, sex, BMI matched patients with same condition of study patients
  • After change sulfonylurea to sitagliptin in case of metformin plus sulfonylurea therapy, no change of blood glucose levels like above or stable HbA1c change within 1% within 2-3 months

Exclusion Criteria:

  • Other causes of increase of blood glucose levels except drug change
  • Patients with history of insulin treatment
  • Patients taking thiazolidinediones, alpha-glucosidase inhibitors, GLP-1 analogue or DPP-4 inhibitors
  • Patients with renal, hepatic dysfunction
  • Patients with diabetic complications such as coronary heart disease, cerebrovascular disease, proliferative diabetic retinopathy or diabetic gastroparesis
  • Patients taking medications affecting glucose level
  Contacts and Locations
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): NCT01449747


Locations
Korea, Republic of
The Catholic University of Korea; St.Paul's Hospital
Seoul, Korea, Republic of, 130-709
The Catholic University of Korea; Seoul St. Mary's Hospital
Seoul, Korea, Republic of, 137-701
Sponsors and Collaborators
The Catholic University of Korea
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Ji Hyun Kim, Dr The Catholic University of Korea
  More Information

Responsible Party: Ji Hyun Kim, Clinical Assistant Professor, The Catholic University of Korea
ClinicalTrials.gov Identifier: NCT01449747     History of Changes
Other Study ID Numbers: CMCENDO-01
First Submitted: September 29, 2011
First Posted: October 10, 2011
Results First Submitted: August 23, 2015
Results First Posted: December 14, 2015
Last Update Posted: December 14, 2015
Last Verified: November 2015

Keywords provided by Ji Hyun Kim, The Catholic University of Korea:
Type 2 diabetes mellitus
Dipeptidyl peptidase IV inhibitors
Glucagon-like peptide 1

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