- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01449747
Pharmacokinetics Study of Dipeptidyl Peptidase 4 Inhibitor to Control Type 2 Diabetes Mellitus
Mechanism of Reduced Response to DPP-4 Inhibitor in Patients With Type 2 Diabetes Mellitus
Study Overview
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.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
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Seoul, Korea, Republic of, 130-709
- The Catholic University of Korea; St.Paul's Hospital
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Seoul, Korea, Republic of, 137-701
- The Catholic University of Korea; Seoul St. Mary's Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Type 2 diabetic patients with less than 15 yrs of disease duration
- BMI between 22-27 kg/m2
HbA1c ≤ 9% at recruitment
- Study group
After change sulfonylurea to sitagliptin in case of metformin and sulfonylurea therapy
- Increase of fasting blood glucose over 20 mg/dL or postprandial glucose over 30 mg/dL within several days or
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
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: study group
sitagliptin hypo-response patients
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Sitagliptin (100mg, per oral) once a day.
Other Names:
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Sham Comparator: control group
sitagliptin response patients
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Sitagliptin (100mg, per oral) once a day.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
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0, 15, 30, 45, 60, 90, 120, 180 min pre and post-dose
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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
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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.
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0, 15, 30, 45, 60, 90, 120, 180 min pre and post-dose
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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
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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.
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0, 15, 30, 45, 60, 90, 120, 180 min pre and post-dose
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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
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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.
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0, 15, 30, 45, 60, 90, 120, 180 min pre and post-dose
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Differences of DPP-4 Activity After Sitagliptin Treatment Between Responder and Non-responder Groups
Time Frame: 0, 15, 30, 45, 60 min post-dose
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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.
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0, 15, 30, 45, 60 min post-dose
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Ji Hyun Kim, Dr, The Catholic University of Korea
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Glucose Metabolism Disorders
- Metabolic Diseases
- Endocrine System Diseases
- Diabetes Mellitus
- Diabetes Mellitus, Type 2
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Protease Inhibitors
- Incretins
- Dipeptidyl-Peptidase IV Inhibitors
- Sitagliptin Phosphate
Other Study ID Numbers
- CMCENDO-01
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