Decreased glucagon levels and decreased insulin secretion after sitagliptin versus mitiglinide administration with similar glycemic levels following an oral glucose load: a randomized crossover pharmaceutical mechanistic study
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Both sitagliptin (SIT) and mitiglinide (MIT) can lower postprandial hyperglycemia. The purpose of this study was to examine differences in insulin and glucagon secretion after SIT or MIT administration when similar levels of plasma glucose (PG) were achieved for both agents following an oral glucose load.
Patients and methods
We directly compared the effects of these two agents in 16 type-2 diabetic patients (M/F = 10/6, age 66 ± 3 years old, HbA1c 6.6 ± 0.5 %). Patients received SIT (50 mg qd for 1 week and 100 mg qd for an additional week) or MIT (10 mg tid for 2 weeks). After 2 weeks, patients crossed over to the other treatment. 75-g oral glucose tolerance tests were conducted before the study and after interventions.
The area under the curve (AUC) up to 180 min for the PG response was similar for both agents. While basal insulin secretion rates (ISR) were similar, incremental AUC of ISR was significantly lower in the SIT treatment (522 ± 108 vs 702 ± 288 pmol/min min, p < 0.01), although the difference between the SIT and MIT treatments in the Matsuda index—which reflects insulin sensitivity—remained nonsignificant. Glucose-stimulated insulin secretion was similarly increased by the MIT and SIT treatments. Suppression of the AUC for glucagon was observed in the SIT treatment, while MIT treatment failed to suppress the glucagon concentration (−432 ± 2322 vs MIT 1116 ± 2520 pg/ml min, p < 0.05). The basal proinsulin/insulin ratio was lower in the SIT treatment (0.23 ± 0.04 vs MIT 0.26 ± 0.36, p < 0.05).
Although either SIT or MIT can be employed to reduce postprandial hyperglycemia, SIT induces changes in hormonal profiles that are more favorable to islet functions than MIT does.
KeywordsSitagliptin Mitiglinide Proinsulin
This work was planned and conducted by the Saitama Incretin Study Group, and was funded via a grant from the Waksman Foundation of Japan, Inc. The authors are members of the Saitama Incretin Study Group, of which Shigehiro Katayama is the president. The number of this clinical trial in the UMIN clinical trial registration system is UMIN000005283. The UMIN Registry has been officially accepted by the ICMJE (International Committee of Medical Journal Editors). Part of the data obtained in this study was presented at the annual meeting of the American Diabetes Association in 2012, and the calculations of insulin secretion rates were presented as an abstract at the annual meeting of the Japan Diabetes Society in 2013.
Conflict of interest
Yoshimasa Aso received lecture fees from Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., and MDS K.K. Shigeharu Katayama received research grants from MSD K.K. and Daiichi Sankyo Pharma Ltd. Yoshitaka Akiyama, Tomoko Morita-Okubo, Natsuko Oshitani, Yuko Ohno, Toshihiko Inukai, Kakei Masafumi, Kawakami Masanobu, Takuya Awata, and Masafumi Matsuda declare that they have no conflict of interest.
Human rights statement and informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its subsequent revision. Informed consent or a substitute for it was obtained from all patients before they were included in the study.
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