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

A Randomized, Controlled Trial

  1. Andreas Fritsche, MD;
  2. Matthias Axel Schweitzer, MD;
  3. Hans-Ulrich Häring, MD; and
  4. the 4001 Study Group*
  1. From Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen; and Aventis, Frankfurt, Germany.

    Abstract

    Background: Patients with type 2 diabetes are often treated with oral antidiabetic agents plus a basal insulin.

    Objective: 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.

    Design: Open-label, randomized, controlled trial.

    Setting: 111 centers in 13 European countries.

    Patients: 695 patients with type 2 diabetes who were previously treated with oral antidiabetic agents.

    Intervention: 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).

    Measurements: Hemoglobin A1c values, blood glucose levels, insulin dose, and body weight.

    Results: 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).

    Conclusion: 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.

    Article and Author Information

    • Grant Support: By Aventis Pharma (Bridgewater, New Jersey), clinical trial registry number HOE 901/4001.

    • Potential Financial Conflicts of Interest:Employment: M.A. Schweitzer (employee of Aventis Pharma; responsible for scientific development of insulin glargine and profiling it with data from clinical studies); Honoraria: A. Fritsche and H.U. Häring (from Aventis Pharma for the presentation of the data in this paper to national and international congresses); Expert testimony: H.U. Häring; Grants received: A. Fritsche and H.U. Häring (travel grants from Aventis Pharma for presentation of the data in this paper to national and international congresses).

    • Requests for Single Reprints: Hans-Ulrich Häring, MD, Medizinische Universitätsklinik, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany; e-mail, Hans-Ulrich.Haering{at}med.uni-tuebingen.de.

    • Current Author Addresses: Drs. Fritsche and Häring: Medizinische Universitätsklinik, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany.

    • Dr. Schweitzer: Aventis Pharma Germany, 65812 Bad Soden am Taunus, Königsteiner Str. 10, Germany.

    • Author Contributions: Conception and design: A. Fritsche, M.A. Schweitzer, H.-U. Häring.

    • Analysis and interpretation of the data: A. Fritsche, M.A. Schweitzer, H.-U. Häring.

    • Drafting of the article: A. Fritsche, M.A. Schweitzer, H.-U. Häring.

    • Critical revision of the article for important intellectual content: A. Fritsche, M.A. Schweitzer, H.-U. Häring.

    • Final approval of the article: A. Fritsche, M.A. Schweitzer, H.-U. Häring.

    • Provision of study materials or patients: A. Fritsche, M.A. Schweitzer.

    • Statistical expertise: M.A. Schweitzer.

    • Obtaining of funding: M.A. Schweitzer.

    • Administrative, technical, or logistic support: M.A. Schweitzer.

    • Collection and assembly of data: A. Fritsche, M.A. Schweitzer.

    Summary for Patients

    • Summaries for Patients: A Comparison of Three Insulin Regimens (Morning Glargine, Bedtime Glargine, or Bedtime Neutral Protamine Hagedorn) in Addition to a Pill for Treating Type 2 Diabetes Ann Intern Med June 17, 2003 138:I-33
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    1. Ann Intern Med June 17, 2003 vol. 138 no. 12 952-959
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