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

• ClinicalTrials.gov Identifier: NCT01449747
• Recruitment Status: Completed
• First Posted: October 10, 2011
• Results First Posted: December 14, 2015
• Last Update Posted: December 14, 2015
• Sponsor: The Catholic University of Korea
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Ji Hyun Kim, The Catholic University of Korea

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Type 2 Diabetes Mellitus	Drug: Sitagliptin	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• 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
• Study Start Date: December 2011
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: July 2015

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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 :

1. 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.

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 70 Years (Adult, Older Adult)
• 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

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
• Other Study ID Numbers: CMCENDO-01
• First Posted: October 10, 2011
• 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; 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