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Insulin Combination Therapy in Type 2 Diabetes Mellitus
- Andreas Fritsche, MD;
- Hans-Ulrich Häring, MD; and
- Matthias Axel Schweitzer, MD
- From Medizinische Universitätsklinik, D-72076 Tübingen, and Aventis Pharma Germany, D-65812 Bad Soden am Taunus, Germany.
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IN RESPONSE:
Drs. Hassan, Hassan, and Gupta and Drs. Mikhail and Wali criticize the open-label design of our study. However, when insulin glargine is compared with NPH insulin, blinding cannot be justified for several reasons. First, NPH insulin is a turbid suspension whereas insulin glargine is a clear solution. Therefore, patients can easily identify the type of insulin they are using whenever the cartridge is transparent (with or without lettering). Second, filling both insulins in nontransparent cartridges can result in the administration of an incorrect dose of insulin; patients must be aware of and in control of the level of insulin in the cartridge. Third, it is necessary to thoroughly mix NPH insulin by rotating the injection device. Not seeing the suspension and mixing conditions can result in an unpredictable action profile of NPH insulin, with an increased risk for hypoglycemia or hyperglycemia (1).
Drs. Mikhail and Wali correctly observe a trend toward higher insulin doses in the morning insulin glargine group. Higher insulin doses may result in better hemoglobin A1c levels, but they are usually accompanied by a higher risk for hypoglycemia. Of note, the use of insulin glargine in this study resulted in better hemoglobin A1c levels and less nocturnal hypoglycemia. The number needed to treat with insulin glargine versus NPH insulin to prevent 1 episode of nocturnal hypoglycemia is 5 for morning insulin glargine and 7 for bedtime insulin glargine. These data are confirmed by recent meta-analyses (2), which concluded that insulin glargine allows a higher insulin dose with lower hemoglobin A1c level but does not increase the risk for hypoglycemia.
The concern of Drs. Mikhail and Wali that the therapies we used did not efficiently reduce postprandial hyperglycemia is not justified by the presented data. Our Figure 3 indicated that the postprandial reduction of hyperglycemia with morning insulin glargine is most effective. Although their concern about a lack of a glimepiride-placebo group is accurate, such a control group would have been unethical because participants were already defined as having had treatment failures with oral antidiabetic drugs. These patients would have been undertreated and most likely would have had poor glycemic control if they received 1 oral antidiabetic agent alone.
Drs. Hassan, Hassan, and Gupta address the question of the clinical significance of our results. If we extrapolate data from the United Kingdom Prospective Diabetes Study (3), patients treated with insulin glargine in the morning (hemoglobin A1c level, 7.8%) would have an approximately 18% reduction in microvascular end points and an approximately 10% reduction in diabetes-related death compared with the group receiving NPH insulin (hemoglobin A1c level, 8.3%). This is in addition to the risk reduction pointed out in our paper for nocturnal hypoglycemia with insulin glargine given in the morning or at bedtime (56% and 42%, respectively) compared with NPH insulin. Recent meta-analyses further demonstrated a 50% risk reduction for severe hypoglycemia with insulin glargine versus NPH insulin (4).
Andreas Fritsche, MD
Hans-Ulrich Häring, MD
Medizinische Universitätsklinik, D-72076 Tübingen, Germany
Matthias Axel Schweitzer, MD
Aventis Pharma Germany, D-65812 Bad Soden am Taunus, Germany
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should:
•Include no more than 300 words of text, three authors, and five references
•Type with double-spacing
•Send three copies of the letter, an authors' form signed by all authors, and a cover letter describing any conflicts of interest related to the contents of the letter.
Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
Annals welcomes electronically submitted letters.
