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ARTICLE

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

Andreas Fritsche, MD; Matthias Axel Schweitzer, MD; Hans-Ulrich Häring, MD, the 4001 Study Group*

17 June 2003 | Volume 138 Issue 12 | Pages 952-959

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 A_1c values, blood glucose levels, insulin dose, and body weight.

Results: Hemoglobin A_1c 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 A_1c 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.

Editors' Notes Context Insulin glargine is a long-acting insulin preparation that has recently become available. Its optimal role in the treatment of type 2 diabetes is being defined. Contribution In this randomized, controlled trial of patients who were taking the sulfonylurea glimepiride, those receiving morning glargine had greater improvement in hemoglobin A1c levels and less frequent nocturnal hypoglycemia than did patients receiving either bedtime neutral protamine Hagedorn (NPH) or bedtime glargine. Implications Morning glargine may be a better option for optimizing glycemic control in patients with type 2 diabetes who are also taking sulfonylureas than is either bedtime glargine or bedtime NPH. –The Editors

 

Author and Article Information

From Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen; and Aventis, Frankfurt, Germany.

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.

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