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BACKGROUND: In subjects with type 2 diabetes mellitus, glycemic control deteroriates while patients use sulfonylurea drugs during the course of the disease. Adjunctive therapy with insulin at this stage requires a lesser daily insulin dose in comparison with insulin monotherapy while restoring desirable glycemic control. However, data regarding direct comparison between various sulfonylureas in this regard are lacking. OBJECTIVE: To examine comparative efficacies of adjunctive therapy with insulin in subjects with type 2 diabetes manifesting lapse of glycemic control while receiving various individual sulfonylurea drugs. METHODS: Four groups of 10 subjects, each presenting with glycosylated hemoglobin (HbA1C) >8.0% while using either tolazamide, glyburide, glipizide Gastrointestinal Therapeutic System (GITS), or glimepiride, were recruited. Two from each group were randomized to receive placebo; the others continued the same drug. Pre-supper subcutaneous 70 NPH/30 regular insulin was initiated at 10 units and gradually increased and adjusted as necessary to attain fasting blood glucose levels between 80 and 120 mg/dL and maintain the same range for 6 months. Fasting plasma glucose, plasma C-peptide, and HbA1C concentrations were determined prior to the addition of insulin and at the end of the study. Daily insulin dose and changes in body weight (BW) were noted at the end of the study, and the number of hypoglycemic events during the last 4 weeks of the study was determined. RESULTS: Daily insulin dose (units/kg BW), weight gain, and number of hypoglycemic events were significantly lower (p < 0.01) in subjects receiving sulfonylureas in comparison with placebo. However, the daily insulin dose alone was significantly lower (p < 0.05) with glimepiride (0.49 ± 0.10; mean ± SE) than with other sulfonylureas (tolazamide 0.58 ± 0.12, glyburide 0.59 ± 0.12, glipizide GITS 0.59 ± 0.14). Finally, a significant correlation (r = 0.68; p < 0.001) was noted between suppression of plasma C-peptide level and the daily insulin dose among all participants. CONCLUSIONS: By lowering the daily insulin dose, sulfonylurea drugs appear to improve the sensitivity of exogenous insulin in subjects with type 2 diabetes mellitus manifesting lapse of glycemic control. Moreover, glimepiride appears to possess a greater insulin-sparing property than other sulfonylureas.