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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*
[+] Article and Author 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@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.


Ann Intern Med. 2003;138(12):952-959. doi:10.7326/0003-4819-138-12-200306170-00006
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Combination therapy with oral antidiabetic drugs during the day and an intermediate-acting NPH insulin given at bedtime has proven to be an effective and feasible therapeutic approach in patients with type 2 diabetes (7). Because of the linear correlation between fasting blood glucose and HbA1c levels, the insulin dose has to be titrated to a fasting blood glucose level of 5.56 mmol/L or less (≤ 100 mg/dL) to achieve good metabolic control (HbA1c level ≤ 7.5%) (13). However, aggressive titration to target is associated with a risk for nocturnal hypoglycemia; this is especially true with NPH insulin because its peak activity occurs approximately 5 hours after injection (7, 20). Since insulin glargine is known to have an action profile with no pronounced peak and a duration of action of approximately 24 hours (1516), we compared the safety and efficacy of a combination therapy with sulfonylurea and bedtime NPH insulin with insulin glargine given either in the morning or at bedtime.

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Figures

Grahic Jump Location
Figure 1.
Trial profile.

NPH = neutral protamine Hagedorn.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Hemoglobin A 1c (HbA 1c ) values, fasting blood glucose levels, body weight, and mean insulin dose measurements.NPH1cPP

These measures were determined at baseline and over the 24-week treatment period with a combination therapy of glimepiride (3 mg) and either neutral protamine Hagedorn ( ) insulin injected at bedtime, insulin glargine injected at bedtime, or insulin glargine injected in the morning. *Decrease in hemoglobin A from baseline: < 0.001 for morning insulin glargine versus bedtime neutral protamine Hagedorn insulin and = 0.008 for morning insulin glargine versus bedtime insulin glargine.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Diurnal blood glucose profile.NPHPPPPPPPPP

Diurnal blood glucose levels were measured at baseline (0 weeks) and before the last visit (24 weeks) in patients who received bedtime neutral protamine Hagedorn ( ) insulin, bedtime insulin glargine, or morning insulin glargine. Profiles at baseline did not differ significantly. values indicate overall differences among treatment groups in the decrease of blood glucose values from baseline. Fasting, > 0.2; after breakfast, = 0.01; lunch, < 0.001; after lunch, < 0.001; dinner, < 0.001; after dinner, < 0.001; bedtime, < 0.001; and 3:00 a.m., = 0.04.

Grahic Jump Location

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Summary 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

The summary below is from the full report titled “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.” It is in the 17 June 2003 issue of Annals of Internal Medicine (volume 138, pages 952-959). The authors are A. Fritsche, M.A. Schweitzer, H.-U. Häring, and the 4001 Study Group.

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