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

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

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.

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