Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin

OBJECTIVE: Nateglinide, a new short-acting D-phenylalanine derivative for treating type 2 diabetes, reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. This study evaluated the pharmacokinetic and pharmacodynamic interactions of nateglinide and metformin in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 12 type 2 diabetic subjects with the following baseline characteristics were enrolled: age, 56 +/- 13 years; BMI, 28.7 +/- 4.5 kg/m2; HbA1c, 8.4 +/- 1.3%; and fasting plasma glucose 13 +/- 2.8 mmol/l. All subjects had been previously treated with glyburide and were switched to metformin monotherapy for 3 weeks before study start. Subjects then randomly received, in combination with 500 mg metformin, either 120 mg nateglinide or placebo before meals for 1 day, followed by the alternate treatment 7 days later. After 1 week of washout from both drugs, subjects received 1 day of open-label nateglinide treatment. Plasma concentrations of glucose, insulin, nateglinide, and metformin were assessed frequently during inpatient periods. RESULTS: Postmeal plasma glucose levels were significantly lower in subjects treated with nateglinide plus metformin than in those treated with either drug alone (P < 0.001), especially after lunch and dinner. Coadministration of nateglinide and metformin did not affect the pharmacokinetics of either drug. All treatments were safe and well tolerated. CONCLUSIONS: Combination therapy with nateglinide and metformin was more effective than either treatment alone and did not result in any pharmacokinetic interactions. Coadministration of nateglinide and metformin appears to be an excellent option for treating patients with type 2 diabetes not controlled with monotherapy.