Backgroud: Although the extended duration of action of insulin glargine supports a convenient once daily injection, the combination with other short acting insulins or oral hypoglycemic agents is required to control postprandial hyperglycemia in type 2 diabetes. The present study was designed to compare the short-term therapeutic efficacy of oral hypoglycemic agents with once daily insulin glargine, switching from a multiple daily injection regimen. METHODS: After control with the intensive regimen (daily lispro insulin and glargine) during 5~7 days, 80 in-patients with type 2 diabetes were randomized and treated with four oral hypoglycemic agents (glimepiride 4 mg qd, metformin 500 mg bid, nateglinide 90 mg tid, or acarbose 100 mg tid) plus once daily insulin glargine during 5 days. Blood glucose concentration was recorded by seven daily estimations (before each meal, 2 hours after each meal, and bedtime). Blood glucose concentrations and area under the curves (AUCs) of blood glucose were compared among four groups. RESULTS: The area under the curve of blood glucose of metformin, glimepiride, nateglinide, and acarbose groups were 165.5 +/- 46.0, 178.5 +/- 36.5, 209.9 +/- 55.1, and 224.9 +/- 55.8 mmol/L/hr respectively. Blood glucose concentrations and area under the curves of blood glucose of glimepiride and metformin groups were significantly lower than those of acarbose group. Also, those of metformin group were significantly lower than those of nateglinide group. Conclusions: Metformin or glimepiride are more effective oral hypoglycemic agent than nateglinide or acarbose in the combination with insulin glargine in type 2 diabetic subjects with failure of sulfonylurea and metformin combination.