J Neurogastroenterol Motil 2013; 19(2): 227-232  https://doi.org/10.5056/jnm.2013.19.2.227
Early Effect of Single-dose Sitagliptin Administration on Gastric Emptying: Crossover Study Using the 13C Breath Test
Takashi Nonaka1, Yusuke Sekino1, Hiroshi Iida1, Eiji Yamada1, Hidenori Ohkubo1, Eiji Sakai1, Takuma Higurashi1, Kunihiro Hosono1, Hiroki Endo1, Tomoko Koide1, Hirokazu Takahashi1, Koji Fujita1, Masato Yoneda1, Ayumu Goto1, Akihiko Kusakabe1, Noritoshi Kobayashi1, Eiji Gotoh2, Shin Maeda1, Atsushi Nakajima1, Chihiro Nosaka3 and Masahiko Inamori4*

1Gastroenterology Division, Yokohama City University Hospital, Yokohama, Japan.

2Department of Medical Education, Yokohama City University School of Medicine, Yokohama, Japan.

3Marketing Department, Kyowa Hakko Kirin Co., Ltd. Tokyo, Japan.

4Office of Postgraduate Medical Education, Yokohama City University Hospital, Yokohama, Japan.

Correspondence to: Correspondence: Masahiko Inamori, MD, PhD. Gastroenterology Division, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Tel: +81-45-787-2640, Fax: +81-45-784-3546, inamorim@med.yokohama-cu.ac.jp
Received: November 6, 2012; Revised: February 21, 2013; Accepted: March 3, 2013; Published online: April 16, 2013.
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Background/Aims

The gastrointestinal motility effects of endogenous incretin hormones enhanced by dipeptidyl peptidase-IV (DPP-IV) inhibitors have not yet been sufficiently investigated. The aim of this study was to determine whether single pre-prandial sitagliptin, the DPP-IV inhibitor, administration might have an effect on the rate of liquid gastric emptying using the C-acetic acid breath test.

Methods

Ten healthy male volunteers participated in this randomized, two-way crossover study. The subjects fasted for overnight and were randomly assigned to receive 50 mg sitagliptin 2 hours before ingestion of the liquid test meal (200 kcal per 200 mL, containing 100 mg C-acetate) or the test meal alone. Under both conditions, breath samples were collected for 150 minutes following the meal. Liquid gastric emptying was estimated by the values of the following parameters: the time required for 50% emptying of the labeled meal (T), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (T), the gastric emptying coefficient and the regression-estimated constants (β and κ), calculated by using the CO breath excretion curve using the conventional formulae. The parameters between the 2 test conditions were compared statistically.

Results

No significant differences in the calculated parameters, including T, T, gastric emptying coefficient or β and κ, were observed between the 2 test conditions.

Conclusions

The present study revealed that single-dose sitagliptin intake had no significant influence on the rate of liquid gastric emptying in asymptomatic volunteers.

Keywords: Breath tests, Gastric emptying, Sitagliptin
Introduction

The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are peptides secreted from the intestine into the circulation in response to food ingestion, and they help manage glycemic control by regulating insulin and glucagon release, slowing gastric emptying, and reducing caloric intake.1-4 Physiologically, the clinical utility of native GLP-1 and GIP is limited because they are rapidly degraded and inactivated by the enzyme dipeptidyl peptidase-IV (DPP-IV).5,6

Inhibition of this enzyme leads to an increase in circulating endogenous GLP-1 and GIP levels. Therefore, DPP-IV inhibitors are a novel therapeutic strategy for type 2 diabetes. Since the release of sitagliptin in 2006, numerous studies have documented the advantages of DPP-IV inhibitors in the management of type 2 diabetes mellitus.7-10 However, the effect of DPP-IV inhibitor-induced enhancement of endogenous incretin hormones on gastrointestinal motility has not yet been sufficiently investigated.11,12 In the present study, the pharmacological effects of pre-prandial single-dose sitagliptin administration on the rate of liquid gastric emptying were examined in healthy volunteers using a 13C-acetic acid breath test.

Materials and Methods

Subjects

The subjects were 10 asymptomatic male volunteers (median age 34 years, range 27-50 years). The height and weight of the subjects were as follows: median height, 169 cm; height range, 162-181 cm; median weight, 64.5 kg; and weight range, 60-92 kg. None of the subjects were habitual drinkers. All were non-smokers and none had a history of gastrointestinal disease or abdominal surgery. None of the subjects was on any routine medication at the time of the study.

The study (Clinical trial registry number: UMIN 000006213) was conducted in accordance with the Declaration of Helsinki. Prior to study initiation, written informed consent was obtained from all participants. The study protocol using the 13C-acetic acid breath test was approved by the Ethics Committee of Yokohama City University School of Medicine.

13C-acetic Acid Breath Test

Ten subjects participated in this randomized, two-way crossover study (Fig. 1). After overnight fasting (at least 8 hours), the subjects received 50 mg sitagliptin orally 2 hours before ingestion of the test meal (sitagliptin condition) or the test meal alone (control condition) in a random sequence. The 2 test conditions were separated by a washout period of at least 7 days.

The test meal was a 200 kcal per 200 mL liquid meal (Racol with milk flavor, Otsuka Pharmaceutical, Co., Ltd., Tokyo, Japan) containing 100 mg of 13C-acetic acid (Cambridge Isotope Laboratories, Inc., USA), and the subjects were requested to consume the meal within 5 minutes.

Gastric emptying was measured using the 13C-acetic acid breath test while the subjects were seated. Breath samples were collected in air bags at baseline (before test meal) and at 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 105, 120, 135 and 150 minutes after completion of the test meal ingestion. The 13CO2/12CO2 ratio in collected breath samples was determined as the difference above baseline using non-dispersive infrared spectrophotometry (POCone, Otsuka Electronics Co., Ltd., Osaka, Japan).

Data Analysis

In accordance with the method reported by Ghoos et al,13 the percentage of 13CO2 recovery in expired breaths per hour (percent dose per hour) against time was fitted to the formula y(t) = atbe-ct by non-linear regression analysis, where y is the percentage of 13C excretion in breath per hour, t is time in hours, and a, b, and c are constants. The time-course of cumulative 13CO2 recovery in expired breaths can be fitted to another formula, z(t) = m(1-e-kt)β, where z is the percentage of the cumulative 13C excretion in expired breaths and also an integral of y(t), m is the cumulative 13CO2 recovery at an infinite time, and β and κ are regression-estimated constants. Using the mathematical curve-fitting technique, β and κ were determined. A larger β indicates slower emptying in the early phase, and a larger κ indicates faster emptying in the later phase. The opposites are also true. The time required for 50% emptying of the labeled meal (T1/2), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (Tlag) and the gastric emptying coefficient (GEC) were calculated as overall measures of gastric emptying: T1/2 = -[ln(1-2-1/β)]/κ, Tlag = (lnβ)/κ and GEC = ln(a).13-15 These parameters were calculated using the Solver procedure in Excel 2010 (Microsoft Corp., Redmond, WA, USA).

Statistical Methods

Statistical evaluation was carried out using the Wilcoxon's signed-rank test. The level of significance was set at P-value < 0.05. We previously estimated that 90% of the subject delayed liquid gastric emptying in sitagliptin condition compare to control condition. The required sample size was therefore estimated to be 10 per group to have 80% power to detect differences at P < 0.05 level. All the statistical analyses were performed using Stat View software (SAS Institute, Cary, NC, USA).

Results

All 10 subjects completed this study, and no adverse events occurred during the study. No significant differences were observed in the T1/2 ([91.8: 72.2-98.4] vs. [94.2: 81.2-106.6]), Tlag ([52.8: 41.7-70.1] vs. [56.0: 44.8-65.5]), GEC ([4.19: 3.76-4.48] vs. [4.17: 3.30-4.52]), β ([2.05: 1.71-3.23] vs. [2.09: 1.86-2.65]) and κ ([0.88: 0.76-1.04] vs. [0.86: 0.66-0.94]) (median: range, control vs. sitagliptin) between the control and experimental conditions (Fig. 2). These results indicated that sitagliptin had no significant effect on the rate of liquid gastric emptying.

Discussion

The present study was conducted to examine the changes in the rate of liquid gastric emptying after single pre-prandial administration of sitagliptin 50 mg during the first 2.5 hours after ingestion of a liquid meal in healthy volunteers. There were no significant differences in any of the liquid gastric emptying parameters measured using the 13C-acetic acid breath test between the 2 test conditions, either ingestion of sitagliptin before the meal or the test meal alone. These results indicate that sitagliptin does not influence the rate of liquid gastric emptying.

After the introduction of DPP-IV inhibitors, numerous studies documenting their advantages in the management for type 2 diabetes mellitus patients have been published.8-10 However, to date, there have been a few studies reporting the pharmacological effects of DPP-IV inhibitors on the gastric emptying rate. In a previous study, DeFronzo et al12 reported that 100 mg sitagliptin once a day for 2 weeks had no effect on the rate of gastric emptying in type 2 diabetes patients by an acetaminophen absorption method. Vella et al11 described that gastric emptying assessed by scintigraphy did not differ between type 2 diabetes patients treated with 50 mg vildagliptin twice a day and placebo for 10 days. Our study was novel in that it examined the effect of single-dose pre-prandial sitagliptin 50 mg on the rate of gastric emptying measured by a 13C-acetic acid breath test using a liquid meal in healthy volunteers.

One of the limitations in this study was the lack of information about actual serum GLP-1 concentrations enhanced by sitagliptin. Steady-state trough concentrations of sitagliptin have been reported to be achieved within 2 to 3 days of administration.14 On the other hand, it has also been reported that single administration of sitagliptin shows an equivalent pharmacokinetic profile compared with once-daily dosing in healthy subjects.14-16 Furthermore, single administration of sitagliptin 50 mg produced by 80% or greater inhibition of DPP-IV activity at 2 hours after administration and over the following 12-hour period, and approximately 2-fold augmentation of postprandial active GLP-1 concentrations compared with placebo in healthy subjects was also observed.15 Herman et al17 reported that single administration of sitagliptin 25 and 200 mg inhibited the enzymatic activity of DPP-IV by 80 to 96% at 2 hours after administration, respectively, and active GLP-1 levels increased greater than 2-fold after both doses in response to an oral glucose tolerance test (OGTT) at 2 hours after administration in patients with type 2 diabetes. They also showed that the near maximal glucose-lowering efficacy of single oral dose of sitagliptin was associated with 80% or greater plasma inhibition of DPP-4 activity. This level of DPP-IV inhibition corresponds to a plasma sitagliptin concentration of 100 nM or greater and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.17

Hence, active GLP-1 concentrations reached potent levels in this present study after single administration of sitagliptin 50 mg. However, these levels of serum GLP-1 concentration enhanced by sitagliptin could be within the physiologic range. Thus, the explanation for the lack of effect on gastric emptying may be due to insufficient concentrations of active GLP-1 to delay gastric emptying, though active GLP-1 concentrations were sufficiently enhanced by sitagliptin to improve glycemic control.

This study was conducted in healthy, normoglycemic male subjects, which limited the extent to which the data can be extrapolated to patients with type 2 diabetes. As mentioned above, on the point of view of drug efficacy, the pharmacokinetic and pharmacodynamics profiles of sitagliptin are reported to be similar in healthy individuals and in those with type 2 diabetes.14-18 However, gastric emptying rates in the type 2 diabetes population have been reported to be delayed, unchanged, or accelerated.19-23 The investigation of gastric emptying rate in healthy subjects might be advantageous for understanding of the natural characteristics of pharmaceutical preparations in contrast to diabetic patients with high heterogeneity in their rates of gastric emptying.

It is also known that there are fundamental differences in the regulatory mechanisms underlying gastric emptying of solids and liquids.24,25 Additionally, the GLP-1 secretory patterns can be modulated by various ingested nutrients.26-28 Solid test meals, as mentioned in previous reports,11,12 may be more useful in clinical application.

Although scintigraphy is the current standard method for assessing gastric emptying,29,30 it is expensive, involves radiation exposure and requires the facilities of a department of nuclear medicine. The evaluation of gastric emptying using the 13C-acetic acid breath test has been developed as a non-radioactive alternative. The subject ingests 13C-labeled acetic acid, which passes through the stomach and is absorbed in the duodenum and superior small bowel. The 13C-labeled acetic acid is then metabolized in the liver and excreted from the lungs as 13CO2. This pathway enables gastric emptying to be measured in a noninvasive manner.31-41 The accuracy of the breath test for measuring gastric emptying has been well supported by several validation studies demonstrating a strong correlation between the breath test and the scintigraphy.13,42-46

Ultimately, as demonstrated in previous studies, sitagliptin had no effect on the rate of liquid gastric emptying in asymptomatic volunteers.

Figures
Fig. 1. The flow of volunteers throughout the trial: two-way crossover study.

Fig. 2. No significant differences were found in the T1/2 (A), Tlag (B), GEC (C), β (D) or κ (E) between the 2 study conditions, indicating that sitagliptin has no significant effect on the rate of gastric emptying. T1/2, the time required for emptying 50% of the labeled meal (minutes); Tlag, the analog to the scintigraphy lag time for 10% emptying of the labeled meal (minutes); GEC, the gastric emptying coefficient; β and κ, the regression-estimated constants.

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