Glimepiride Combined with Morning Insulin Glargine, Bedtime Neutral Protamine Hagedorn Insulin, or Bedtime Insulin Glargine in Patients with Type 2 Diabetes

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Abstract
Patients with type 2 diabetes are often treated with oral antidiabetic agents plus a basal insulin. To investigate the efficacy and safety of glimepiride combined with either morning or bedtime insulin glargine or bedtime neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. Open-label, randomized, controlled trial. 111 centers in 13 European countries. 695 patients with type 2 diabetes who were previously treated with oral antidiabetic agents. Randomization to treatment with morning insulin glargine, bedtime NPH insulin, or bedtime insulin glargine for 24 weeks in addition to 3 mg of glimepiride. The insulin dose was titrated by using a predefined regimen to achieve fasting blood glucose levels of 5.56 mmol/L or lower ( 100 mg/dL). Hemoglobin A1c values, blood glucose levels, insulin dose, and body weight. Hemoglobin A1c levels improved by 1.24% (two-sided 90% CI, 1.10% to 1.38%) with morning insulin glargine, by 0.96% (CI, 0.81% to 1.10%) with bedtime insulin glargine, and by 0.84% (CI, 0.69% to 0.98%) with bedtime NPH insulin. Hemoglobin A1c improvement was more pronounced with morning insulin glargine than with NPH insulin (0.40% [CI, 0.23% to 0.58%]; P = 0.001) or bedtime insulin glargine (0.28% [CI, 0.11% to 0.46%]; P = 0.008). Baseline to end-point fasting blood glucose levels improved similarly in all three groups. Nocturnal hypoglycemia was less frequent with morning (39 of 236 patients [17%]) and bedtime insulin glargine (52 of 227 patients [23%]) than with bedtime NPH insulin (89 of 232 patients [38%]) (P < 0.001). The risk for nocturnal hypoglycemia was lower with glimepiride in combination with morning and bedtime insulin glargine than with glimepiride in combination with bedtime NPH insulin in patients with type 2 diabetes. Morning insulin glargine provided better glycemic control than did bedtime insulin glargine or bedtime NPH insulin. *For members of the 4001 Study Group, see the Appendix.