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Accepted Manuscript

Effects of linagliptin monotherapy compared with voglibose on postprandial blood glucose responses in Japanese patients with type 2 diabetes: Linagliptin Study of Effects on Postprandial blood glucose (L-STEP)

Yoshio Fujitani, Shimpei Fujimoto, Kiyohito Takahashi, Hiroaki Satoh, Takahisa Hirose, Toru Hiyoshi, Masumi Ai, Yosuke Okada, Masahiko Gosho, Tomoya Mita, Hirotaka Watada

PII: S0168-8227(16)30605-2 DOI: http://dx.doi.org/10.1016/j.diabres.2016.09.014 Reference: DIAB 6750

To appear in: Diabetes Research and Clinical Practice

Received Date: 18 June 2016 Revised Date: 18 August 2016 Accepted Date: 2 September 2016

Please cite this article as: Y. Fujitani, S. Fujimoto, K. Takahashi, H. Satoh, T. Hirose, T. Hiyoshi, M. Ai, Y. Okada, M. Gosho, T. Mita, H. Watada, Effects of linagliptin monotherapy compared with voglibose on postprandial blood glucose responses in Japanese patients with type 2 diabetes: Linagliptin Study of Effects on Postprandial blood glucose (L-STEP), Diabetes Research and Clinical Practice (2016), doi: http://dx.doi.org/10.1016/j.diabres. 2016.09.014

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Fujitani et al.

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Effects of linagliptin monotherapy compared with voglibose on Effects of linagliptin monotherapy compared with voglibose on Effects of linagliptin monotherapy compared with voglibose on Effects of linagliptin monotherapy compared with voglibose on postprandial blood glucose responses in Japanesepostprandial blood glucose responses in Japanesepostprandial blood glucose responses in Japanesepostprandial blood glucose responses in Japanese patients with patients with patients with patients with type 2 diabetestype 2 diabetestype 2 diabetestype 2 diabetes:::: LinagliptinLinagliptinLinagliptinLinagliptin Study of Effects on Postprandial Study of Effects on Postprandial Study of Effects on Postprandial Study of Effects on Postprandial blood glucose (Lblood glucose (Lblood glucose (Lblood glucose (L----STEP)STEP)STEP)STEP)

Yoshio Fujitani1,3, Shimpei Fujimoto6, Kiyohito Takahashi7, Hiroaki Satoh8,

Takahisa Hirose9, Toru Hiyoshi10, Masumi Ai11, Yosuke Okada12, Masahiko Gosho13,

Tomoya Mita1,4, and Hirotaka Watada1,2,3,4,5

1 Department of Metabolism & Endocrinology, Juntendo University Graduate

School of Medicine, Tokyo, Japan

2 Center for Beta-Cell Biology and Regeneration, Juntendo University Graduate

School of Medicine, Tokyo, Japan

3 Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate

School of Medicine, Tokyo, Japan

4 Center for Molecular Diabetology, Juntendo University Graduate School of

Medicine, Tokyo, Japan

5 Sportology Center, Juntendo University Graduate School of Medicine, Tokyo,

Japan

6 Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School,

Kochi University, Nankoku-shi, Kochi, Japan

7 Takahashi Kiyohito Clinic, Hakodate, Hokkaido, Japan

8 Department of Nephrology, Hypertension, Diabetology, Endocrinology, and

Metabolism, Fukushima Medical University, Fukushima, Japan

9 Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine,

Toho University School of Medicine, Tokyo, Japan

10 Japanese Red Cross Medical Center, Tokyo, Japan

11 Department of Insured Medical Care Management, Tokyo Medical and Dental

University (TMDU), Tokyo, Japan

12 First Department of Internal Medicine, School of Medicine, University of

Occupational and Environmental Health, Kitakyushu-shi, Japan

13 Department of Clinical Trial and Clinical Epidemiology, Faculty of Medicine,

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University of Tsukuba, Ibaraki, Japan

Corresponding author

Hirotaka Watada, MD, PhD

Department of Metabolism & Endocrinology, Juntendo University Graduate School

of Medicine, 2-1-1 Hongo, Bunkyo-ku, 113-8421 Tokyo, Japan

Tel.: +81 358021579

E-mail address: hwatada@juntendo.ac.jp

Fujitani et al.

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AbstarctAbstarctAbstarctAbstarct

Aims: To compare the efficacy on glycemic parameters between a 12-week

administration of once-daily linagliptin and thrice-daily voglibose in Japanese

patients with type 2 diabetes.

Methods: In a multi-center, randomized, parallel-group study, 382 patients with

diabetes were randomized to the linagliptin group (n = 192) or the voglibose group

(n = 190). A meal tolerance test was performed at weeks 0 and 12. Primary outcomes

were the change from baseline to week 12 in serum glucose levels at 2 hours during

the meal tolerance test, HbA1c levels, and serum fasting glucose levels, which were

compared between the 2 groups.

Results: Whereas changes in serum glucose levels at 2 hours during the meal

tolerance test did not differ between the groups, the mean change in HbA1c levels

from baseline to week 12 in the linagliptin group (–0.5 ± 0.5% [–5.1 ± 5.4

mmol/mol]) was significantly larger than in the voglibose group (–0.2 ± 0.5%

[–2.7 ± 5.4 mmol/mol]). In addition, there was significant difference in changes in

serum fasting glucose levels (–0.51 ± 0.95 mmol/L in the linagliptin group vs. −0.18

± 0.92 mmol/L in the voglibose group, P < 0.001). The incidences of hypoglycemia,

serious adverse events (AEs), and discontinuations due to AEs were low and similar

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in both groups. . . . However, gastrointestinal AEs were significantly lower in the

linagliptin group (1.05% vs. 5.85%; P = 0.01).

Conclusions: These data suggested that linagliptin monotherapy had a stronger

glucose-lowering effect than voglibose monotherapy with respect to HbA1c and

serum fasting glucose levels, but not serum glucose levels 2 hours after the start of

the meal tolerance test.

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1. 1. 1. 1. IntroductionIntroductionIntroductionIntroduction

Early type 2 diabetes is characterized by postprandial hyperglycemia[1].

Postprandial hyperglycemia plays an important role in the development of

cardiovascular complications in patients with type 2 diabetes mellitus (T2DM)[2]

and people with impaired glucose tolerance (IGT) [3]. Postprandial hyperglycemia

also plays an important role in accelerating pancreatic β-cell failure by imposing

increased insulin secretory demands on pancreatic β cells, leading to the

development of T2DM in patients with IGT. Thus, postprandial glycemic excursion

is a favorable treatment target for patients with early stage T2DM, with respect to

the inhibition of both disease progression and cardiovascular complications.

Alpha-glucosidase inhibitors (α-GIs) prevent the digestion of carbohydrates, and

reduce postprandial blood glucose excursion [4, 5]. The α-GI acarbose was shown to

improve postprandial hyperglycemia and impaired endothelial function in patients

with T2DM [6, 7] and to attenuate the risk of cardiovascular events in patients with

T2DM [8] and in individuals with IGT [4]. Voglibose, another α-GI, when used

together with lifestyle modifications, can prevent the development of T2DM in

high-risk Japanese individuals with IGT [5]. Supported by evidence from these

clinical trials, α-GIs have been widely prescribed as a primary treatment in Japan

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for patients with T2DM that cannot be controlled by lifestyle modifications.

On the other hand, dipeptidyl peptidase (DPP)-4 inhibitors prevent the degradation

of endogenous glucagon-like peptide-1 (GLP-1), which in turn enhances

glucose-dependent insulin secretion from pancreatic β cells, and reduces glucagon

secretion from α cells, which potentially suppresses postprandial glycemic

excursions[9-11]. DPP-4 inhibitors are generally well tolerated and do not affect

body weight.

Linagliptin is a highly selective, once-daily oral DPP-4 inhibitor used worldwide in

more than 80 countries, including the United States, Europe, and Japan for the

treatment of patients with T2DM. Whereas many other DPP-4 inhibitors that are

available today are excreted mostly via the renal route [12], linagliptin is selectively

excreted via the bile and gut, making it suitable for use without dose adjustment in

patients with renal dysfunction [13]. In clinical studies, linagliptin was reported to

be as effective on glycemic parameters as metformin and sulfonylureas [14]. The

safety profile of linagliptin was more favorable than that of a sulfonylurea

regarding hypoglycemia and body weight gain. A composite endpoint (consisting of a

combination of HbA1c < 7% without hypoglycemia and without weight gain) was

achieved more frequently in patients treated with linagliptin in comparison with

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patients treated with the sulfonylurea glimepiride [14]. Linagliptin had a better

safety profile than glimepiride with respect to a combined cardiovascular endpoint,

including stroke [14].

To date, the effect of two types of diabetes agents, namely, the DPP-4 inhibitor

linagliptin, and the α-GI voglibose on postprandial glucose response in patients

with T2DM has not been directly compared. We hence conducted a randomized

prospective multicenter study that we named the Linagliptin Study of Effects on

Postprandial blood glucose (L-STEP) to compare the effects of linagliptin and

voglibose on postprandial hyperglycemia, as assessed by the meal tolerance test and

other glycemic parameters in patients with T2DM and those with insufficient

glycemic control despite diet and exercise.

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2. 2. 2. 2. MethodsMethodsMethodsMethods

2.1 2.1 2.1 2.1 Study design and patientsStudy design and patientsStudy design and patientsStudy design and patients

Japanese patients with T2DM who periodically visited the outpatient clinic of the

44 institutions in Japan listed in the supplementary material (Appendix S1) were

asked to participate in this study. The first patient was enrolled on October 12, 2012,

and the last patient visit occurred on April 16, 2014.

The study enrolled patients with T2DM who were 20 years of age or older and who

had inadequate glycemic control (haemoglobin A1c [HbA1c] 6.2–9.4% [44.2–79.2

mmol/mol] in those previously untreated with oral anti-diabetes drugs (OADs)

irrespective of sex; and 6.2–9.4% [44.2–79.2 mmol/mol] after washout in those

already receiving one or two OADs for ≥ 12 weeks). Key exclusion criteria were 1)

type 1 or secondary diabetes, 2) presence of severe infectious disease either before or

after surgery, or severe trauma, 3) history of myocardial infarction, angina pectoris,

cerebral stroke, or cerebral infarction, 4) severe liver dysfunction (aspartate

aminotransferase [AST] ≥ 100 IU/L), 5) moderate or severe heart failure (New York

Heart Association stage III or greater), 6) receiving treatment with an incretin

preparation, such as other DPP-4 inhibitors, at the start of the study, 7) received

treatment with any type of antidiabetes drug within the previous 3 months and/or a

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history of known intolerance, allergy, or hypersensitivity to voglibose or any other

concomitant drug, 8) women who were pregnant, lactating, or possibly pregnant,

and those planning to become pregnant during the study period, 9) those who

required the administration of oral or intravenous corticosteroids, 10) cancer patients,

history of open abdominal surgery or ileus and 11) patients judged as ineligible by

the clinical investigators. All patients gave written consent to participate in the

study, and the study was approved by the Institutional Review Board of each

participating center. This study is registered on the University Hospital Medical

Information Network Clinical Trials Registry (study no. UMIN000008591), which is

a non-profit organization in Japan, and meets the requirements of the International

Committee of Medical Journal Editors.

2.2. 2.2. 2.2. 2.2. RandomizRandomizRandomizRandomization and study interventionation and study interventionation and study interventionation and study intervention

Patients were registered at the administration office of the L-STEP trial via the

internet, and once enrolled, they were randomly assigned in equal numbers to

either the linagliptin group or the voglibose group. Randomization was performed

using a dynamic allocation method based on HbA1c levels and body mass index

(BMI) at baseline.

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After the 4-week screening period, linagliptin was administered orally at 5 mg once

daily in the linagliptin group and voglibose was administered orally at 0.2 mg/meal

thrice daily in the voglibose group.

2.3. 2.3. 2.3. 2.3. Study outcomes Study outcomes Study outcomes Study outcomes

The primary endpoints of the present study were the change from baseline in

postprandial serum glucose levels at 2 hr after the start of the meal tolerance test,

HbA1c levels, and fasting serum glucose levels during the 12 weeks of treatment.

Measurements were performed at the start of the study and repeated after 12

weeks.

The secondary endpoints included (i) serum glucose levels at 1 hr after start of the

meal tolerance test, (ii) secretion of insulin and glucagon during the meal tolerance

test, (iii) effects on body weight and blood pressure (BP), (iv) effect on serum lipid

profile, and (v) safety of the regimen, which were compared between the 2 groups.

2.4. 2.4. 2.4. 2.4. Evaluation of sEvaluation of sEvaluation of sEvaluation of safety and cardiovascular eventsafety and cardiovascular eventsafety and cardiovascular eventsafety and cardiovascular events

All adverse events (AEs) were recorded during the study for the sake of patient

safety. AEs were defined as any untoward medical occurrence in a clinical trial

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subject who was administered a medicinal product. AEs did not necessarily have a

causal relationship with the treatment. The association between AEs and the study

medication was classified as either being associated with or not associated with the

study drug by one of the investigators. All associated AEs that resulted in a

withdrawal of the subject from the study were monitored until resolution. Serious

AEs were defined as death or life-threatening events that required inpatient

hospitalization, caused prolongation of existing hospitalization, or even resulted in

persistent or significant disability/incapacity that required intervention to prevent

permanent impairment or damage.

2.5. 2.5. 2.5. 2.5. Sample sizeSample sizeSample sizeSample size

Iwamoto et al. reported changes in 2 hr postprandial glucose after a 12-week

treatment with sitagliptin or voglibose in Japanese patients with T2DM [15]. Based

on the results of that study, we estimated the changes in 2 hr postprandial glucose

after 12 weeks for the linagliptin group and voglibose group to be 45 mg/dL and 25

mg/dL, respectively. Standard deviations of the changes were estimated as 60

mg/dL. Under these assumptions, we estimated the target sample size of 190 in

each group with 90% power and alpha of 0.05. With the additional assumption of a

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5% dropout in the course of the study, the target number of enrolled patients was

set to 190 for each group.

2.6. 2.6. 2.6. 2.6. SSSStatistical analysistatistical analysistatistical analysistatistical analysis

Efficacy was analyzed regardless of adherence, using an intention-to-treat (ITT)

approach. Results are presented as means ± SD for continuous variables, or

numbers (proportion) of patients for categorical variables.

For the all data, comparisons between the groups were assessed with the Student's

t-test or Wilcoxon rank-sum test for continuous variables and the Fisher's exact test

for categorical variables. Changes from baseline to treatment visits were assessed

with the one-sample t-test or Wilcoxon signed-rank test within the group. In

addition, we carried out the mixed effects model for repeated measures (MMRM) for

the change from baseline to week 12 in blood glucose level with a model including

treatment group, time after the meal tolerance test (0, 1, 2 hr), interactions between

treatment group and time, and baseline glucose levels; an unstructured covariance

structure was used to model the covariance within-subject variability. The number

and percentage of patients reporting AEs were presented by treatment group and

compared between the two treatment groups using the Fisher's exact test. All

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statistical tests were two-sided with a 0.05 significance level. All analyses were

performed using the SAS software version 9.4 (SAS Institute, Cary, NC).

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3. 3. 3. 3. ResultsResultsResultsResults

3.1. Patient characteristics3.1. Patient characteristics3.1. Patient characteristics3.1. Patient characteristics

Figure 1 shows a flowchart of the trial profile of the present study. A total of 382

patients were recruited and randomly assigned to either the linagliptin group

(n = 192) or the voglibose group (n = 190). Two subjects of each group were

excluded based on the aforementioned criteria. A total of 190 patients of the

linagliptin group and 188 patients of the voglibose group were analyzed with

respect to safety. Twelve patients, who had never taken study medication were

excluded from the ITT analyses. Accordingly, of the 382 subjects randomized,

366 were included in the ITT analysis (188 in the linagliptin group and 178 in

the voglibose group). Two subjects with AEs, including one patient with cancer

were withdrawn from the linagliptin group and 13 subjects including 5 patients

with AEs and 8 patients with non-compliance of medication were withdrawn

from the voglibose group.

The baseline characteristics of the ITT populations are presented in Table 1.

The two groups were well balanced at baseline, with comparable mean age, sex,

and HbA1c levels. BMI tended to be slightly larger in the voglibose group than

in the linagliptin group, although the difference between the groups was not

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statistically significant (P = 0.055).

3.2. 3.2. 3.2. 3.2. Primary Primary Primary Primary eeeendpointndpointndpointndpoint

There was no significant difference in serum glucose concentrations at 2 hr between

the linagliptin and voglibose group both at baseline and at the endpoint (Figure

2A,B). The mean change in serum glucose level after 2 hr was similar in the two

treatment groups (linagliptin group -1.94 ± 2.27 mmol/L, voglibose group -2.00 ±

2.15 mmol/L [P = 0.82] (Figure 2C); primary endpoint of this study). At baseline,

there was no difference in mean HbA1c levels between the two groups. At the

endpoint (week 12), the HbA1c level was 6.5 ± 0.6% [47.8 ± 6.8 mmol/mol] in the

linagliptin group and 6.7 ± 0.7% [49.5 ± 7.7 mmol/mol] in the voglibose group, and

the difference was significant (P = 0.033; Table 2). Over 12 weeks, both linagliptin

and voglibose significantly reduced HbA1c levels relative to the baseline (P < 0.001).

However, the change in HbA1c levels from baseline to week 12 in the linagliptin

group was significantly greater than that in the conventional treatment group

(linagliptin group: –0.5 ± 0.5% [–5.1 ± 5.4 mmol/mol], voglibose group –0.2 ± 0.5%

[–2.7 ± 5.4 mmol/mol], P < 0.001; Table 2).

Figure 2 shows the serial changes in mean serum glucose concentrations during a

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meal tolerance test at baseline (Figure 2A) and at the endpoint (12 weeks) (Figure

2B). At the endpoint, fasting serum glucose levels tended to be lower in the

linagliptin group than in the voglibose group (linagliptin group 7.1±1.2 mmol/L,

voglibose group 7.3±1.4 mmol/L [P = 0.091]; Figure 2B). In addition, a reduction in

fasting serum glucose levels (from the baseline to endpoint, week 12) in the

linagliptin group was slightly but significantly larger than that observed in the

voglibose group (linagliptin group －0.51±0.95 mmol/L, voglibose group －0.18±

0.92 mmol/L [P < 0.001]; Figure 2C). The results of the MMRM method for the

changes in the serum glucose levels (fasting P < 0.001, 2hr P = 0.73) was not

different from the results by Student's t-test.

3.3. 3.3. 3.3. 3.3. Secondary Secondary Secondary Secondary eeeendpointndpointndpointndpoint

At baseline, the mean glucose concentration at 1hr was higher in the linagliptin

group than in the voglibose group (linagliptin group 13.6±2.6mmol/L, voglibose

group 13.0±2.5 mmol/L [P = 0.018]; Figure 2A). At the endpoint (week 12), the

mean glucose concentration at 1 hr was also higher in the linagliptin group than in

the voglibose group (linagliptin group 11.7±2.2 mmol/L, voglibose group 10.5±2.2

mmol/L [P < 0.001]; Figure 2B). The reduction in mean serum glucose concentration

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at 1 hr from baseline to week 12 in the voglibose group was significantly larger than

that observed in the linagliptin group (linagliptin group －1.98±1.88 mmol/L ,

voglibose group －2.45±1.88 mmol/L [P = 0.019]; Figure 2C). For the changes in the

serum glucose levels at 1 hr, the result of the MMRM method (P = 0.011) was

similar to the result by Student's t-test, as well as fasting and at 2 hr as mentioned

above.

3.4. 3.4. 3.4. 3.4. Insulin and Insulin and Insulin and Insulin and gggglucagon lucagon lucagon lucagon rrrresponses esponses esponses esponses dddduring uring uring uring the the the the mmmmeal eal eal eal ttttolerance olerance olerance olerance ttttestestestest

At baseline, there was no difference in insulin secretory profile during the meal

tolerance test between the linagliptin group and the voglibose group (Figure 2D). At

the endpoint (week 12), although there was no difference in fasting plasma insulin

concentrations between the two groups, postprandial plasma insulin concentrations

were significantly higher in the linagliptin group than in the voglibose group (P  =

0.002 at 1hr and P < 0.001 at 2 hr, Figure 2E). Figure 2F compares the mean changes

in plasma insulin concentrations from the baseline to the endpoint during the meal

tolerance test. Whereas significant effects of linagliptin treatment on postprandial

insulin peak excursion was observed, 12-week voglibose treatment significantly

decreased postprandial plasma insulin concentrations compared with linagliptin

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treatment (P < 0.001 at both of 1 and 2 hr; Figure 2F).

At baseline, there were no differences in plasma glucagon concentrations during the

meal tolerance test between the two groups (Figure 2G). At the endpoint

postprandial plasma glucagon concentrations were significantly lower in the

linagliptin group than in the voglibose group (P < 0.001 at 1 hr and P < 0.001 at 2 hr;

Figure 2H). Accordingly, the increment in plasma glucagon concentrations from the

baseline to the endpoint was significantly larger in the voglibose group than in the

linagliptin group at 1 hr (P  = 0.002) and at 2 hr (P < 0.001) (Figure 2I).

3.5. 3.5. 3.5. 3.5. Body weight and BPBody weight and BPBody weight and BPBody weight and BP

Subjects in the voglibose group showed a significant loss of body weight (−1.1 ± 2.1

kg, P < 0.001) from baseline, whereas it was unchanged in the linagliptin group (－

0.2±2.1kg, P=0.32) (Table 2). There was no difference in systolic blood pressure

(SBP) and in diastolic blood pressure (DBP) between the two groups at baseline,

which was also true at the endopoint (Table 2).

3.6. 3.6. 3.6. 3.6. Lipid Lipid Lipid Lipid pppprofilerofilerofilerofilessss

There was no difference in the baseline levels of fasting triglyceride (TG),

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remnant-like particle (RLP) cholesterol, total cholesterol (TC), low-density

lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol

between the two groups (Table 2). At the endopoint, no differences were also

observed in these lipid parameters between the two groups (Table 2). In addition, no

significant changes from baseline were observed in these parameters in both groups,

except that a significant increase was observed in LDL cholesterol levels in the

voglibose group (2.96 ± 0.80 mmol/L at baseline to 3.06 ± 0.85 mmol/L at 12 weeks,

P  = 0.003; Table 2).

3.7. 3.7. 3.7. 3.7. SafetySafetySafetySafety and and and and ttttolerabilityolerabilityolerabilityolerability

Over the 12-week treatment period, no meaningful differences among treatment

groups were observed in the incidence of AEs (Table 3). Symptomatic hypoglycaemia,

which is an AE of special interest, occurred only in one patient of each group. Four

serious AEs were reported. In the linagliptin group, one patient developed rectal

cancer and another developed acute myocardial infarction, and in the voglibose

group, one patient developed colorectal polyps and another developed lung cancer.

No deaths occurred during the study.

Linagliptin treatment resulted in clinically significant reductions in the liver injury

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biomarker AST (−1 ± 8 IU/L, P  = 0.039) and alanine aminotransferase (ALT)

(−3 ± 8 IU/L, P  < 0.001; Table 2). Subjects in the linagliptin group exhibited a

significant increase in amylase levels from baseline (+5 ± 16 IU/L, P  < 0.001),

although the value was within normal range. In the linagliptin group, serum

creatinine levels were slightly but significantly increased, and eGFR levels were

significantly decreased from baseline, although the changes in these parameters did

not show any statistically significant difference between the groups (Table 2). The

adherence to medication in the linagliptin group was higher than in the voglibose

group (98% ± 4% vs. 93% ± 11%, P  < 0.001). In the voglibose group, eight subjects

were withdrawn from the study due to medication non-compliance, whereas no such

cases were observed in the linagliptin group (Figure 1).

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4. 4. 4. 4. DiscussionDiscussionDiscussionDiscussion

This 12-week prospective multicenter study compared the efficacy, safety, and

adherence to treatment of linagliptin with voglibose in Japanese T2DM patients

inadequately controlled by diet and exercise. Voglibose was selected as the

comparator in this study because it has been widely prescribed for patients with

T2DM in East Asian countries, including China and Japan to improve postprandial

hyperglycemia[5, 16-18]. In this study, linagliptin showed a higher efficacy than

voglibose in providing greater reductions in HbA1c and fasting serum glucose levels

from baseline, whereas there was no significant difference in changes in 2 hours

glucose levels after the start of the meal tolerance test. Of note, voglibose showed

higher efficacy than linagliptin in achieving a greater reduction in 1 hour postmeal

glucose levels, further confirming the potent effect of α-glucosidase inhibitors on

the suppression of postprandial glucose excursion.

Defects in the secretion and action of insulin are the two major

abnormalities leading to the onset of T2DM, and any intervention that attenuates

insulin resistance or protects pancreatic β cells may help to prevent or delay the

progression of the disease [19]. Voglibose was found to reduce postprandial insulin

secretion through an attenuation of postmeal glycemic excursions, and these

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changes were considered to reduce the stress on overworked β cells [5]. On the other

hand, the absence of any significant effects of linagliptin treatment on insulin peak

excursion suggest that insulin secretion is maintained despite a concomitant

reduction in postmeal glucose levels. This suggests improved responsiveness of the

pancreatic β cells to glucose levels. This possibility likely explains why no changes

in insulin levels have been observed by linagliptin treatment, and is in agreement

with a previous study indicating that systemic insulin sensitivity can be improved

by linagliptin [20].

It is well known that glucagon secretion shows characteristic abnormalities

in T2DM. Patients with T2DM often have increased fasting hyperglucagonemia and

exhibit exaggerated postprandial responses [21, 22]. GLP-1 can suppress glucagon

secretion and maintains this ability also in patients with T2DM [10]. It has been

reported that the insulinotropic effect induced by GLP-1 and inhibition of glucagon

secretion contribute equally to the glucose-lowering effect of GLP-1 in patients with

T2DM [23]. Thus, it is reasonable to consider that both the suppression of glucagon

levels and maintenance of insulin levels can explain the glucose-lowering effects of

linagliptin in this study. Of note, the increase in GLP-1 levels by DPP-4 inhibitors

does not impair the counter-regulatory response of glucagon to hypoglycemia [24].

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Linagliptin was shown to be associated with a low risk of hypoglycemia when

administered as a monotherapy. Indeed, none of the patients developed severe

hypoglycemia while receiving linagliptin in this study, further confirming the low

rate of hypoglycemia observed in previous studies [25, 26]. An unexpected finding of

this study was that glucagon concentrations during a meal tolerance test,

particularly 2 hours after meal loading, was increased from baseline in the

voglibose-treated group (Figure 2I, +13.5 ± 24.3 pg/mL, P < 0.001). We do not at

present have a clear explanation for this phenomenon. However, one possible

explanation might be the reduction of insulin secretion by voglibose (Figure 2), as

insulin signaling from β cells can inhibit glucagon secretion from α cells in a

paracrine fashion [27]. Further studies are required to gain mechanistic insight into

this phenomenon.

Given that postprandial hyperglycemia is implicated in the increased risk

of cardiovascular disease [3], it is assumed that α-glucosidase inhibitors exhibit risk

reduction of cardiovascular events in subjects with IGT due to effective attenuation

of postprandial hyperglycemia [28]. Linagliptin was superior to voglibose in

achieving greater reduction in HbA1c and fasting glucose levels without

hypoglycemia. Linagliptin also exhibited comparable effects to voglibose in

Fujitani et al.

24

controlling postprandial glucose excursion. In this respect, if treatment is initiated

at an early stage of T2DM, linagliptin may potentially be associated with reduced

cardiovascular risk by smoothing postprandial blood glucose excursion, together

with avoiding body weight gain and hypoglycemia [29]. In clinical studies,

linagliptin was more favorable regarding its effects on cardiovascular safety profiles

compared with combination therapy of metformin and sulfonylureas. Gallwitz et al.

reported that linagliptin had a better safety profile regarding a combined

cardiovascular endpoint, including stroke, although the number of subjects was

small and the observation period was short in that study [14]. In previous studies,

DPP-4 inhibition with saxagliptin (the SAVOR-TIMI study) [30] or alogliptin (the

EXAMINE study) [31] did not alter the rate of ischemic events, although these

studies targeted T2DM patients with high cardiovascular risk. To evaluate the

cardiovascular safety of linagliptin for T2DM patients, a long-term, randomized,

placebo-controlled prospective study recruiting a large number of T2DM patients

with cardiovascular risk (the CARMELINA study) is currently underway [32].

When treating T2DM, an improvement in glycemic control, particularly

achieved by increased insulin secretion, is often associated with body weight gain.

DPP-4 inhibitors generally do not affect body weight, which may be explained by

Fujitani et al.

25

the minimal changes in treatment-induced fasting and postprandial insulin levels

[33, 34]. In this study, significant weight loss was observed in the voglibose group,

but not in the linagliptin group. This may be associated with the reduced insulin

levels that were observed in the voglibose group. A reduction in postprandial insulin

levels after 12 weeks of voglibose treatment has also been reported previously [15].

A possible explanation is that voglibose increases insulin sensitivity. Indeed, a

previous report showed that voglibose treatment of Japanese patients with T2DM

results in increased insulin sensitivity [35].

In the present study, patients taking linagliptin (once daily dosing) showed

better medication adherence than patients taking voglibose (thrice daily dosing).

Recent clinical studies evaluated the effect of dosing frequency (once daily, twice

daily, thrice daily, and four times daily) on medication adherence in patients with

T2DM. The results of these studies consistently showed that once daily dosing was

associated with a higher rate of adherence compared with more than once daily

dosing [36-39]. Collectively, it is anticipated that once daily dosing of linagliptin will

result in higher adherence compared with diabetes medications with

multiple-dosing schedules, and should eventually lead to better outcomes of

long-term glycemic control and improvement in the quality of life of the patients.

Fujitani et al.

26

There are several limitations to the present study. First, as this study was

limited to subjects without OADs, it is not possible to conclude that the effects of

linagliptin and voglibose on glycemic parameters found in this study can be

generalized to patients with OADs, particularly metformin, which is widely used as

a first line therapy. These agents may have additional effects when used in

combination. Second, we could not clarify differences in long-term benefits or risks

between the agents because this was a short-term study. Third, analyses were not

controlled for multiple testing. Therefore, our results should be interpreted with

caution.

In conclusion, our findings demonstrate the overall safety and tolerability

of the oral administration of linagliptin for the treatment of Japanese patients with

T2DM. Treatment with linagliptin monotherapy should become a valuable

treatment option for Japanese patients with T2DM, providing clinically meaningful

improvement in glycemic control without causing any unacceptable side effects,

with weight neutrality, and a low risk of hypoglycaemia.

Fujitani et al.

27

AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements

This study was funded by Boehringer Ingelheim and Eli Lilly. The authors wish to

thank the study investigators (Appendix S1) for their contributions to this study.

K. T., H. S., T. H. and Y. O. were trial investigators and participated in data

collection. Y. F., T. M. and H. W. prepared the first draft of the manuscript. M. G.

was responsible for the statistical considerations in the analysis and trial design. S.

F., T. H. and M. I. were responsible for medical oversight during the trial and trial

design. All authors participated in reviewing and interpreting the data and

providing comments and revisions to the manuscript. All authors approved the final

version of the manuscript and take full responsibility for the content.

Fujitani et al.

28

ConflictConflictConflictConflictssss of of of of iiiinterestnterestnterestnterest

HW has received honoraria for scientific lectures from MSD, Eli Lilly, Takeda,

Novartis, Dainippon Sumitomo, Sanofi and Daiichi Sankyo, and also research funds

from MSD, Eli Lilly, Takeda, Kowa, Mochida, Sanwakagaku, Novo Nordisk, Kissei,

Novartis, Boehringer Ingelheim, AstraZeneca, Astellas, Tanabe Mitsubishi,

Dainippon Sumitomo, Abbott, Sanofi Aventis, Pfizer, and Daiichi Sankyo. YF has

received grant support from Takeda, MSD, and Nippon Eli Lilly. YF has also acted

as spokespersons for Novartis Pharma, Nippon Eli Lilly, MSD, and Sanofi Aventis.

SF has received has received lecture fees from Ono pharmaceutical Co., Ltd., and

also grant/research support from Astellas Pharma Inc., Takeda Pharmaceutical Co.,

Ltd., MSD K.K., AstraZeneca K.K., Eli Lilly Japan K.K., Ono Pharmaceutical Co.,

Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co.,

Ltd. KT has received lecture fees from Nippon Boehringer Ingelheim Co., Ltd., Eli

Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., Sanofi K.K., Eisai Co., Ltd., Ono

Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., ASKA Pharmaceutical.

Co., Ltd., Mitsubishi Tanabe Pharma Factory Ltd., Shionogi & Co., Ltd., Astellas

Pharma Inc., Novo Nordisk Pharma Ltd., Kyowa Hakko Kirin Co., Ltd. HS has

received grant/research support from Genzyme Japan K.K., Asahi Kasei Co., Eisai

Fujitani et al.

29

Co., Ltd., Abbott Japan Co.,Ltd., Torii Pharmaceutical Co., Ltd., Nippon Boehringer

Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Otsuka Pharmaceutical Co., Ltd.,

Terumo Co., Sumitomo Dainippon Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd.,

Mochida Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., MSD K.K.,

Novo Nordisk Pharma Ltd., Kissei Pharmaceutical Co., Ltd., Astellas Pharma Inc.

and also lecture fees from Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K.,

Sanofi-Aventis K.K., Taisho Toyama Pharmaceutical Co., Ltd., Kowa

Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., AstraZeneca K.K., Ono

Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Kyowa Hakko

Kirin Co., Ltd., Mochida Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co.,

MSD K.K., Novo Nordisk Pharma Ltd., Kissei Pharmaceutical Co., Ltd., Astellas

Pharma Inc. TH has received lecture fees from Sanofi K.K., Eli Lilly Japan K.K.,

Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co.,

Ltd., Mitsubishi Tanabe Pharma Co., MSD K.K., Sumitomo Dainippon Pharma Co.,

Ltd., Novartis Pharma K.K., Kissei Pharmaceutical Co., Ltd., Nippon Boehringer

Ingelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K. and also

research funds from AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd. and

grant/research support from Sanofi K.K., Eli Lilly Japan K.K., Novo Nordisk

Fujitani et al.

30

Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd.,

Mitsubishi Tanabe Pharma Co., Sumitomo Dainippon Pharma Co., Ltd., Kissei

Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Astellas Pharma

Inc., Johnson & Johnson K.K., Ono Pharmaceutical Co., Ltd., AstraZeneca K.K. MA

has received lecture fees from MSD K.K. and Sanofi K.K. YO has received lecture

fees from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Ono Pharmaceutical

Co., Ltd., Mitsubishi Tanabe Pharma Co., Bayer Yakuhin, Ltd, Novo Nordisk

Pharma Ltd., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Daiichi

Sankyo Co., Ltd., Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Kowa

Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co.,Ltd. and also research

funds from Kowa Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Bayer

Yakuhin, Ltd, MSD K.K. MG has received manuscript fee from Kowa Co., Ltd. All

other authors declare no conflicts of interest.

Fujitani et al.

31

Figure legendsFigure legendsFigure legendsFigure legends

Figure 1.Figure 1.Figure 1.Figure 1.

Flowchart of the patient recruitment process.

Figure 2Figure 2Figure 2Figure 2....

Treatment effects on blood glucose levels during the meal tolerance test at baseline

(A) and after 12 weeks of treatment (B). Changes in blood glucose levels from

baseline are shown in (C). Data are shown as the mean ± SD. * P < 0.05, ** P < 0.01,

*** P < 0.001

Treatment effects on insulin levels during the meal tolerance test at baseline (D)

and after 12 weeks of treatment (E). Changes in insulin levels from baseline are

shown in (F). Data are shown as the mean ± SD. * P < 0.05, ** P < 0.01, *** P <

0.001

Treatment effects on glucagon levels during the meal tolerance test at baseline (G)

and after 12 weeks of treatment (H). Changes in glucagon levels from baseline are

shown in (I). Data are shown as the mean ± SD. * P < 0.05, ** P < 0.01, *** P < 0.001

Fujitani et al.

32

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Registration and

randomization n = 382

Linagliptin group n = 192

Voglibose group n = 190

Safety analysis set n = 190

Safety analysis set n = 188

ITT set n = 188

ITT set n = 178

2 patients (conflicted with exclusion criteria)

2 patients ( conflicted with exclusion criteria)

2 patients (with no medication record)

10 patients (with no medication record)

Figure 1. Flow chart of the patient recruitment process

Study discontinued: 2 patients

Adverse events: 2 Cancer: 1 Other : 1

Non-compliance with medication: 0

Withdrawal: 0 patients

Study discontinued: 13 patients

Adverse events: 5 Cancer: 0 Other : 5

Non-compliance with medication: 8

Withdrawal: 0 patients

Figure 2.

(A) Blood glucose: Baseline (B) Blood glucose: Week 12 (C) Blood glucose: Change from baseline

(D) Insulin: Baseline (E) Insulin: Week 12 (F) Insulin: Change from baseline

(G) Glucagon: Baseline (H) Glucagon: Week 12 (I) Glucagon: Change from baseline

*

*** ***

*

** *** ***

*** ***

** ***

***

Fujitani et al.

36

Table 1.Table 1.Table 1.Table 1.

Patient demographics and baseline characteristics

Variable Linagliptin,

n = 188

Voglibose,

n = 178

P-value

Age (years) 60.8 ± 11.9 61.1 ± 11.8 0.80

Sex (n [%])

0.92

Female 84 (44.7) 81 (45.5)

Male 104 (55.3) 97 (54.5)

Diabetic neuropathy (n [%]) 14 (7.0) 7 (4.0) 0.18

BMI (kg/m2) 24.9 ± 4.3 25.8 ± 4.5 0.055

HbA1c (%) 7.0 ± 0.7 6.9 ± 0.6 0.37

HbA1c (mmol/mol) 52.9 ± 7.4 52.2 ± 6.6 0.37

Data are expressed as frequency (n [%]) or the mean ± SD.

Fujitani et al.

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Table 2.Table 2.Table 2.Table 2. Efficacy endpoints in the linagliptin and voglibose groups in the ITT population

Variable

Baseline (n) Week 12 (n) Change from

baseline (n)

P-value

(intragroup)

HbA1c (%)

Linagliptin

7.0 ± 0.7 (188) 6.5 ± 0.6 (186) -0.5 ± 0.5 (186) < 0.001

Voglibose

6.9 ± 0.6 (178) 6.7 ± 0.7 (173) -0.2 ± 0.5 (173) < 0.001

P-value

(intergroup) 0.37 0.033 < 0.001

HbA1c (mmol/mol)

Linagliptin

52.9 ± 7.4 (188) 47.8 ± 6.8 (186) -5.1 ± 5.4 (186) < 0.001

Voglibose

52.2 ± 6.6 (178) 49.5 ± 7.7 (173) -2.7 ± 5.4 (173) < 0.001

P-value

(intergroup) 0.37 0.033 < 0.001

Body weight (kg)

Linagliptin

64.9 ± 13.1 (188) 64.8 ± 13.6 (186) -0.2 ± 2.1 (186) 0.32

Voglibose

67.1 ± 14.8 (178) 66.2 ± 14.6 (173) -1.1 ± 2.1 (173) < 0.001

P-value

(intergroup) 0.12 0.33 < 0.001

BMI (kg/m2)

Linagliputin

24.9 ± 4.3 (188) 24.9 ± 4.5 (186) -0.1 ± 0.8 (186) 0.27

Voglibose

25.8 ± 4.5 (178) 25.4 ± 4.4 (173) -0.4 ± 0.8 (173) < 0.001

P-value

(intergroup) 0.055 0.25 < 0.001

SBP (mmHG)

Linagliptin

132 ± 18 (187) 131 ± 18 (186) -1 ± 15 (185) 0.49

Voglibose

131 ± 18 (175) 130 ± 16 (173) -1 ± 15 (170) 0.29

P-value

(intergroup) 0.55 0.45 0.75

DBP (mmHG)

Linagliputin

78 ± 12 (187) 78 ± 12 (186) 0 ± 10 (185) 0.67

Voglibose

78 ± 11 (175) 77 ± 11 (173) -1 ± 10 (170) 0.29

P-value

(intergroup) 0.70 0.55 0.67

AST (IU/L)

Linagliptin

27 ± 12 (187) 25 ± 12 (186) -1 ± 8 (185) 0.039

Voglibose

27 ± 14 (178) 25 ± 12 (172) -1 ± 10 (172) 0.10

Fujitani et al.

38

P-value

(intergroup) 0.92 0.94 0.90

ALT (IU/L)

Linagliptin

30 ± 22 (187) 27 ± 20 (186) -3 ± 13 (185) < 0.001

Voglibose

30 ± 24 (178) 31 ± 21 (172) 0 ± 16 (172) 0.84

P-value

(intergroup) 0.99 0.098 0.026

γ-GTP (IU/L)

Linagliptin

50 ± 54 (184) 45 ± 43 (182) -4 ± 37 (180) 0.11

Voglibose

50 ± 53 (174) 46 ± 51 (170) -1 ± 30 (168) 0.53

P-value

(intergroup) 0.93 0.88 0.41

Serum creatinine (µmol/L)

Linagliptin

62.8 ± 16.1 (186) 64.1 ± 16.6 (186) 1.4 ± 6.8 (184) 0.007

Voglibose

64.0 ± 15.1 (177) 64.1 ± 14.7 (172) 0.2 ± 5.9 (171) 0.61

P-value

(intergroup) 0.46 1.00 0.098

Amylase (IU/L)

Linagliptin

73.0 ± 28.9 (176) 77.0 ± 27.2 (180) 5 ± 16 (172) < 0.001

Voglibose

70.5 ± 26.4 (172) 68.8 ± 25.0 (173) -1 ± 12 (167) 0.12

P-value

(intergroup) 0.39 0.004 < 0.001

Urinary albumin (mg/g･Cr)

Linagliptin

12.3 [6.9, 26.3] (179) 11.5 [6.7, 27.7] (182) -0.5 [-6.8, 3.5] (173) 0.11

Voglibose

13.8 [7.0, 27.6] (171) 11.2 [7.1, 24.7] (166) -0.6 [-8.4, 3.5] (159) 0.10

P (intergroup)

0.61 0.98 0.89

TG (mmol/L)

Linagliptin 1.41 ± 0.99 (185) 1.45 ± 1.62 (185) 0.04 ± 1.33 (182) 0.68

Voglibose 1.48 ± 0.99 (177) 1.37 ± 0.90 (173) -0.10 ± 0.77 (172) 0.077

P-value

(intergroup) 0.50 0.53 0.22

RLP (mmol/L)

Linagliptin 0.13 ± 0.15 (188) 0.15 ± 0.29 (186) 0.02 ± 0.26 (186) 0.42

Voglibose 0.13 ± 0.11 (178) 0.12 ± 0.08 (173) -0.01 ± 0.11 (173) 0.35

P-value

(intergroup) 0.77 0.21 0.29

Fujitani et al.

39

TC (mmol/L)

Linagliptin 5.23 ± 0.86 (175) 5.18 ± 0.90 (179) -0.3 ± 13.4 (170) 0.76

Voglibose 5.12 ± 0.90 (171) 5.14 ± 0.93 (168) 0.8 ± 12.5 (165) 0.40

P-value

(intergroup) 0.23 0.64 0.42

LDL-C (mmol/L)

Linagliptin 3.05 ± 0.76 (184) 3.03 ± 0.74 (185) 2.3 ± 28.1 (181) 0.27

Voglibose 2.96 ± 0.80 (177) 3.06 ± 0.85 (172) 6.0 ± 25.8 (171) 0.003

P-value

(intergroup) 0.28 0.71 0.20

HDL-C (mmol/L)

Linagliptin 1.56 ± 0.45 (186) 1.56 ± 0.45 (186) 0.7 ± 13.1 (184) 0.47

Voglibose 1.49 ± 0.45 (178) 1.47 ± 0.44 (173) -0.9 ± 12.7 (173) 0.37

P-value

(intergroup) 0.19 0.080 0.25

eGFR (ml/min/1.73m2)

Linagliptin 81.2 ± 18.2 (186) 79.4 ± 18.2 (186) -1.6 ± 8.7 (184) 0.01

Voglibose 78.6 ± 17.3 (177) 78.2 ± 16.6 (172) -0.6 ± 8.0 (171) 0.36

P-value

(intergroup) 0.18 0.50 0.24

Data are expressed as the mean ± SD, except for Urinary albmin that was shown as median [Q1, Q3].

"Change from baseline" for TC, LDL-C, and HDL-C are shown as the percentage change between the

baseline and week 12. For the others, it is shown as the change in actual value between the baseline

and week 12.

Fujitani et al.

40

Table 3Table 3Table 3Table 3. Summary of adverse events (AEs) reported during 12 weeks of treatment

with either linagliptin or voglibose in the ITT population.

Linagliptin Voglibose P-value

n 190 188

All AEs 16 27 0.08

Influenza 1 0 1

Lumbosacral strain 1 0 1

Hyperglycemia 0 1 0.5

Vertigo 0 2 0.25

Chills 1 0 1

Gastroenteritis 0 3 0.12

Gastric pain 0 1 0.5

Diarrhea 1 2 0.62

Common cold 1 4 0.21

Liver dysfunction 1 4 0.21

Acute bronchitis 1 0 1

Acute upper respiratory

inflammation 0 1 0.5

Acute myocardial infarction 1 1 1

Heartburn 0 1 0.5

Feeling of hunger 1 0 1

General fatigue 0 1 0.5

Trigeminal neuralgia 0 1 0.5

Poor appetite 0 1 0.5

Epigastric pain 1 0 1

Pyelonephritis 1 0 1

Anterior communicating artery

aneurysm 1 0 1

Itching sensation 1 0 1

Colorectal polyps 0 1 0.5

Rectal cancer 1 0 1

Hypoglycemia 1 1 1

Heaviness of the head 1 0 1

Headache 0 1 0.5

Lung cancer 0 1 0.5

Fujitani et al.

41

Rash 0 1 0.5

Fever 1 0 1

Abdominal pain 0 2 0.25

Abdominal symptom 0 1 0.5

Abdominal distension 0 2 0.25

Constipation 1 0 1

Abdominal wind 1 0 1

Drug eruption 1 0 1

Knee pain 1 0 1

Nausea 0 2 0.25

Any gastrointestinal event

including pain 2 11 0.01

Gastrointestinal pain 0 3 0.12