This study was performed to examine the efficacy and safety of the rapid- and short-acting insulinotropic SUR ligand mitiglinide given as add-on therapy for 52 weeks in type 2 diabetic patients whose blood glucose was insufficiently controlled by pioglitazone monotherapy. Type 2 diabetic patients aged > or = 20 years with postprandial plasma glucose (PPG1 or 2) > or = 200 mg/dL and glycated hemoglobin (HbA(1C)) 6.5-<9.0% despite receiving pioglitazone 15-45 mg/day were additionally treated with concomitant mitiglinide 10 mg tid p.o. for a total treatment period of 52 weeks. In 171 patients recruited, HbA(1C) was significantly reduced from 7.64 +/- 0.77% at baseline to 6.84 +/- 0.73%, 6.64 +/- 0.64%, 6.67 +/- 0.57% and 6.81 +/- 0.65% at weeks 16, 28, 40, and 52, respectively. Over half the patients achieved HbA(1C) target of <7.0%, and one third <6.5%. Significant reductions in fasting plasma glucose (FPG) and PPG 1 and 2 hours after a meal versus baseline were noted at all time-points evaluated. The most frequently noted adverse reactions were hypoglycemic symptoms, weight gain, and peripheral edema (all mild). In type 2 diabetic patients combination therapy with mitiglinide and pioglitazone exerted significant long-term improvements in HbA(1C), FPG, and PPG and was well tolerated. This drug combination therapy is a promising means of alleviating insufficient pancreatic insulin secretion and insulin resistance.