Andreas Fritsche, MD; Matthias Axel Schweitzer, MD; Hans-Ulrich Hring, MD; and the 4001 Study Group*
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. Hring (from Aventis Pharma for the presentation of the data in this paper to national and international congresses); Expert testimony: H.U. Hring; Grants received: A. Fritsche and H.U. Hring (travel grants from Aventis Pharma for presentation of the data in this paper to national and international congresses).
Requests for Single Reprints: Hans-Ulrich Hring, MD, Medizinische Universittsklinik, Otfried-Mller-Str. 10, D-72076 Tbingen, Germany; e-mail, Hans-Ulrich.Haering@med.uni-tuebingen.de.
Current Author Addresses: Drs. Fritsche and Hring: Medizinische Universittsklinik, Otfried-Mller-Str. 10, D-72076 Tbingen, Germany.
Dr. Schweitzer: Aventis Pharma Germany, 65812 Bad Soden am Taunus, Knigsteiner Str. 10, Germany.
Author Contributions: Conception and design: A. Fritsche, M.A. Schweitzer, H.-U. Hring.
Analysis and interpretation of the data: A. Fritsche, M.A. Schweitzer, H.-U. Hring.
Drafting of the article: A. Fritsche, M.A. Schweitzer, H.-U. Hring.
Critical revision of the article for important intellectual content: A. Fritsche, M.A. Schweitzer, H.-U. Hring.
Final approval of the article: A. Fritsche, M.A. Schweitzer, H.-U. Hring.
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.
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.
Fritsche A, Schweitzer MA, Hring H, and the 4001 Study Group*. 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. Ann Intern Med. 2003;138:952–959. doi: 10.7326/0003-4819-138-12-200306170-00006
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Published: Ann Intern Med. 2003;138(12):952-959.
Cardiology, Coronary Risk Factors, Diabetes, Endocrine and Metabolism.
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