Supplemental Table 1. Questionnaire and check list items in the JPA DEM project

Age (years old) Concomitant drug b

Sex hypoglycemic agent*/ nonhypoglycemic agent/

Male/ female nothing

Height (cm) *Sulphonylurea (gliclazide/ glibenclamide/

Weight (kg) glimepiride/ others) rapid insulin secretagogue/

Smoking habit biguanide/ thiazolidine/ α-glucosidase inhibitor/

Never smoker/ past smoker/ current smoker insulin/ GLP-1 analog/ others

Alcohol consumption Diseases under pharmacotherapy b

Non drinker/ <1 per week/ 1-3 per week/ Renal disease/ liver disease/ heart disease/

>3 per week dyslipidemia/ hypertension/ asthma/ others/

HbA1c a (%) nothing

First day of prescription of DPP-4 inhibitor Nonpharmacologic therapy b

Previous day of prescription of DPP-4 inhibitor Diet therapy/ exercise therapy/ nothing

DPP-4 inhibitor currently taking b Adverse drug reaction b, c

Glactiv® 25,50,100mg/ Januvia® 25, 50, 100mg/ Dizziness/ blurred vision/ weakness, tiredness/

Nesina® 6.25, 12.5, 25mg/ Equa® 50mg/ drowsiness/ hunger/ palpitation/ shakiness/

Trazenta® 5mg/ Liovel® LD, HD perspiration/ abdominal discomfort/ abdominal

Daily dose (tablets) distension/ abdominal pain/ constipation/

Taking time b diarrhea/ nausea/ gastritis/ myalgia/ headache/

In the morning/ at noon/ in the evening/ nasopharyngitis/ stomatitis/ periodontitis/ rash/

at bed time/ others edema/ cough/ vertigo/ arrhythmia/ others/ nothing

a Latest value reported by patient.

b Multiple answers allowed.

c The question was phased, “Have there been any changes since the previous prescription?” with caution

against leading the patient to make a particular response.

JPA = Japan Pharmaceutical Association; DEM =Drug Event Monitoring; DPP-4 = dipeptidyl peptidase-4

GLP-1 = glucagon-like peptide-1

Supplemental Table 2. Characteristics of the included and excluded patients

Included patients a

N = 1550

Excluded patients a

N= 452P-value

Female (%) 44.3 40.3 0.15

Age (years) 68.0 ± 11.8 68.6 ± 12.0 0.30

BMI b (kg/m2) 24.8 ± 4.3 24.1 ± 3.0 0.19

HbA1c b (%) 6.8 ± 1.0 6.9 ± 1.1 0.48

Alcohol consumption b (%) 0.12

Non-drinking 52.1 57.3

Less than 1 time /week 18.9 19.9

1-3 times /week 8.8 9.9

More than 3 times /week 20.3 12.9

Smoking b (%) 0.11

Never 60.8 62.7

Past 23.4 17.0

Current 15.8 20.3

Liver disease b (%) 4.1 3.0 0.48

Renal disease b (%) 3.4 5.1 0.19

The ratio of daily dose to

maximum dose c 0.59 ± 0.24 0.61 ± 0.25 0.17

Other DM medication use (%) 65.7 61.7 0.13

a The values are presented as the percentage of subjects or the mean ± standard deviation.

b Some data were missing.

c To assess the daily doses of the four DPP-4 inhibitors in the same scale, we divided the

prescribed daily dose by the approved maximum dose for each subject.

BMI = body mass index; DM = diabetes mellitus

Supplemental Table 3. Symptoms identified according to each type of DPP-4 inhibitor therapy a

Sitagliptin Alogliptin Vildagliptin

M (402) C (767) M (65) C (176) M (61) C (75)

Hypoglycemic symptoms 10 (2.5%) 15 (2.0%) 3 (4.6%) 6 (3.4%) 0 (0%) 0 (0%)

Non-hypoglycemic symptoms 11 (2.7%) 28 (3.7%) 0 (0%) 13 (7.4%) 1 (1.6%) 4 (5.3%)

a　Due to the small sample size (n=4) and lack of reports of adverse symptoms, the data for linagliptin are not

shown.

M = monotherapy; C = combination therapy

Supplemental Table 4. Crude odds ratios for the symptoms of hypoglycemia

With symptoms a

N =34

Without symptoms a N

= 1,516

Crude ORs [95%

CI]

Age (years old) 68.2 ± 10.7 68.0 ± 11.8 1.00 [0.97-1.03]

Female 58.8 43.9 1.82 [0.91-3.64]

BMI b (%) 25.4 ± 4.7 24.8 ± 4.3 1.03 [0.95-1.11]

Ever smoker 44.1 39.1 1.23 [0.62-2.44]

Alcohol consumption c

Less than 1 time /week 20.6 18.9 1.39 [0.55-3.47]

1-3 times /week 11.8 8.7 1.72 [0.56-5.29]

More than 3 times /week 26.5 20.1 1.67 [0.72-3.90]

HbA1c b (%) 6.7 ± 1.0 6.8 ± 1.0 0.84 [0.56-1.26]

Duration from the first prescription of DPP-4

inhibitor to the interview (month)10.8 ± 7.0 9.9 ± 6.5 1.02 [0.97-1.08]

Duration from the last prescription to the

interview (days)26.2 ± 12.3 28.8 ± 22.6 0.99 [0.97-1.02]

DPP-4 inhibitor currently taking

Sitagliptin 73.5 75.5 0.90 [0.42-1.95]

Alogliptin 26.5 15.3 1.99 [0.92-4.32]

Vildagliptin 0.0 9.0 -

Linagliptin 0.0 0.3 -

The ratio of daily dose to maximum dose d

0.62 ± 0.27 0.59 ± 0.24 1.66 [0.43-6.49]

Concomitant hypoglycemic agent use 61.8 65.8 0.84 [0.42-1.69]

Sulphonylurea 50.0 43.8 1.28 [0.65-2.53]

Biguanide 14.7 21.0 0.65 [0.25-1.69]

α-glucosidase inhibitor 11.8 14.2 0.81 [0.28-2.31]

Thiazolidine 8.8 8.8 1.01 [0.30-3.34]

Rapid insulin secretagogue 0.0 1.6 -

Insulin 2.9 1.9 1.55 [0.21-11.75]

GLP-1 analog 0.0 0.1 -

Number of concomitant hypoglycemic agent 0.88 ± 0.91 0.92 ± 0.82 0.94 [0.62-1.43]

Concomitant non-hypoglycemic agent use 73.5 59.7 1.88 [0.87-4.05]

Diseases under pharmacotherapy 91.2 88.1 1.39 [0.42-4.60]

Renal disease 2.9 3.4 0.87 [0.12-6.49]

Liver disease 11.8 4.0 3.24 [1.11-9.48]

Heart disease 14.7 15.4 0.95 [0.36-2.47]

Dyslipidemia 41.2 39.9 1.05 [0.53-2.10]

Hypertension 61.8 63.2 0.94 [0.47-1.89]

Asthma 2.9 2.8 1.06 [0.14-7.96]

Diet or exercise therapy 75.9 63.9 1.78 [0.75-4.19]

a The values are presented as the percentage of subjects or the mean ± standard deviation.

b Some data were missing.

c Compared with non-drinker.

d To assess daily doses of four DPP-4 inhibitors in the same scale, we divided the prescribed daily dose by the

approved maximum dose in every subject.

OR = odds ratio; CI = confidence interval; BMI = body mass index; DPP-4 = dipeptidyl peptidase-4;

GLP-1 = glucagon-like peptide-1

Supplemental Table 5. Crude and adjusted odds ratios for the nonhypoglycemic symptoms

With symptoms a

N = 57

Without symptoms a N

= 1,493

Crude ORs

[95% CI]

Adjusted ORs b

[95% CI]

Other DM medication use 78.9 65.2 2.00 [1.05-3.82] 1.97 [1.03-3.78]

Female 56.1 43.8 1.64 [0.96-2.80] 1.67 [0.98-2.87]

Age 67.3 ± 10.6 68.0 ± 11.8 1.00 [0.97-1.02] 1.00 [0.97-1.02]

a The values are presented as the percentage of subjects or the mean ± standard deviation.

b Adjusted for other factors listed in this table.

OR = odds ratio; CI = confidence interval; DM = diabetes mellitus

Supplemental Table 6. Daily dose (mg) of sitagliptin

With

hypoglycemic

symptoms a

Without

hypoglycemic

symptoms a

P-value

With

nonhypoglycemic

symptoms a

Without

nonhypoglycemic

symptoms a

P-value

All subjects 48.5 ± 16.3 51.2 ± 16.2 0.412 51.3 ± 12.8 51.1 ± 16.3 0.950

Female 53.3 ± 16.0 50.6 ± 15.7 0.504 51.2 ± 12.4 50.6 ± 15.8 0.874

Male b 41.3 ± 14.5 51.7 ± 16.5 0.048 51.4 ± 13.5 51.5 ± 16.6 0.975

With liver disease 50.0 ± 0.0 48.1 ± 13.9 0.784 50.0 ± 0.0 48.0 ± 14.0 0.757

a The values are presented as the mean ± standard deviation

b Among 11 male subjects who complained of hypoglycemic symptoms, 10 were ever smokers and four had liver

diseases.