Supplementary material to:
“The influence of tofogliflozin on treatment-related quality of life in patients with type 2 diabetes mellitus”
List of the institutional review boards (alphabetical order):
Research Ethics Committee of Ikeda Municipal Hospital (IRB11000019) Research Ethics Committee of Jiyugaoka Medical Clinic (IRB)
Research Ethics Committee of Juntendo Tokyo Koto Geriatric Medical Center (IRB11000134)
Research Ethics Committee of Juntendo University Graduate School of Medicine (IRB 11000367)
Research Ethics Committee of Kansai Rosai Hospital (IRB11000182) Research Ethics Committee of Kawasaki Hospital
Research Ethics Committee of Kawasaki Medical School (IRB11000120) Research Ethics Committee of NakaKinen Clinic (IRB12000112)
Research Ethics Committee of National Hospital Organization Osaka (IRB11000763)
Research Ethics Committee of Nissay Hospital (IRB1800075)
Research Ethics Committee of Osaka General Medical Center (IRB11000754) Research Ethics Committee of Osaka Police Hospital (IRB14000008)
Research Ethics Committee of Osaka Rosai Hospital (IRB11000716)
Research Ethics Committee of Osaka University Graduate School of Medicine (IRB15000038)
Research Ethics Committee of University of Occupational and Environmental Health, Japan (IRB11000040)
Eligibility criteria of the study subjects Inclusion criteria:
1) Japanese with T2DM and inadequate glycemic control (HbA1c ≥ 6 % but < 9 %) but the inability to achieve the blood glucose level stated in the Diabetes Treatment Guideline of 2014-2015 despite being on drugs other than SGLT2 inhibitors with diet and physical therapy or on diet and physical therapy only for at least 12 weeks or patients who received treatment with SGLT2 inhibitors in the past but who have not used SGLT2 inhibitors for at least 12 weeks before signing their consent form.
2) No changes (including new prescriptions) in the patient’s antidiabetic, antithrombotic, antihypertensive medication or a therapeutic agent for dyslipidemia for at least 12 weeks before signing consent form.
3) Age 30–74 years at the time of giving consent.
4) Being able to provide informed consent.
Exclusion criteria:
1) Type 1 or secondary diabetes.
2) Patients who are within the perioperative period or those with a serious infection or injury.
3) A history of myocardial infarction, angina, stroke, or cerebral infarction.
4) Severe renal dysfunction or end-stage renal failure (estimated glomerular filtration rate < 30 mL/min/1.73 m2).
5) Serious liver functional impairment (aspartate aminotransferase ≥ 100 U/L).
6) Moderate-to-severe heart failure (class 3 or worse based on the New York Heart Association Functional Classification).
7) Urinary tract or genital infection.
8) Pregnant, possibly pregnant, nursing, or planning to conceive a child.
9) History of hypersensitivity to the study drug.
10) Present or past history of a malignant tumor (exceptions: patients not on medication for malignant tumor and no recurrence of the disease without recurrence risks during this study were allowed to participate).
11) Patients prohibited from using tofogliflozin.
12) Other ineligibility, as determined by an investigator.
Supplementary Table S1. Clinical characteristics of patients with and without DTR-QOL data
Parameters Patients with DTR-QOL data
(n = 252)
Patients without DTR-QOL data (n = 87)
p value
Sex (males) (%) 152 (60.3) 46 (52.9) 0.26
Age (years) 61.7 ± 9.5 59.3 ± 9.2 0.041
Current smoking 49 (19.4) 18 (20.9) 0.76
Body mass index (kg/m2) 26.8 ± 5.4 27.6 ± 4.6 0.25
Waist circumference (cm) 93.2 ± 12.6 (n = 236) 94.1 ± 10.7 (n = 67) 0.59
Duration of diabetes (years) 12.6 ± 8.6 11.5 ± 7.5 0.34
HbA1c (%) 7.3 ± 0.7 7.5 ± 0.8 0.12
Fasting blood glucose (mmol/L) 7.8 ± 1.8 7.8 ± 1.8 (n = 83) 0.95
C-peptide (ng/mL) 1.93 ± 1.14 2.12 ± 1.35 (n = 82) 0.21
Hypertension 140 (55.6) 53 (60.9) 0.45
Systolic blood pressure (mmHg) 133.7 ± 16.2 (n = 247) 133.8 ± 15.4 (n = 83) 0.98
Diastolic blood pressure (mmHg) 78.0 ± 10.9 (n = 247) 79.5 ± 9.1 (n = 83) 0.28
Dyslipidemia 161 (63.9) 68 (78.2) 0.017
Total cholesterol (mmol/L) 5.01 ± 0.77 (n = 248) 4.75 ± 0.78 (n = 80) 0.010
LDL cholesterol (mmol/L) 2.95 ± 0.68 (n=250) 2.70 ± 0.63 0.002
HDL cholesterol (mmol/L) 1.39 ± 0.35 1.42 ± 0.30 0.45
Triglyceride (mmol/L) 1.38 (0.97, 1.91) 1.23 (0.98, 1.68) (n = 83) 0.35
Diabetic retinopathy 47 (18.8) (n = 250) 14 (16.3) (n = 86) 0.75
Diabetic nephropathy 79 (31.3) 22 (25.3) 0.34
Use of glucose-lowering agents 224 (88.9) 81 (93.1) 0.31
Metformin 132 (52.4) 59 (67.8) 0.013
Sulfonylurea 62 (24.6) 19 (21.8) 0.66
Glinides 16 (6.3) 4 (4.6) 0.79
Thiazolidinediones 34 (13.5) 7 (8.0) 0.25
α-Glucosidase inhibitor 33 (13.1) 16 (18.4) 0.22
DPP-4 inhibitors 133 (52.8) 37 (42.5) 0.11
GLP-1 R agonists 18 (7.1) 17 (19.5) 0.002
Insulin 58 (23.0) 14 (16.1) 0.22
Use of antihypertensive drugs 128 (50.8) 46 (52.9) 0.80
Angiotensin-converting enzyme inhibitors 5 (2.0) 3 (3.4) 0.34
Angiotensin II receptor blockers 110 (43.7) 36 (41.4) 0.80
Direct renin inhibitor 2 (0.8) 0 (0.0) 1.00
Calcium channel blocker 75 (29.8) 26 (29.9) 1.00
Diuretic drugs 16 (6.3) 6 (6.9) 0.81
α-Adrenergic receptor antagonist 1 (0.4) 1 (1.1) 0.45
β-Adrenergic receptor antagonist 5 (2.0) 1 (1.1) 1.00
Others 0 (0.0) 0 (0.0) –
Use of lipid-lowering agents 122 (48.4) 59 (67.8) 0.002
Statins 110 (43.7) 46 (52.9) 0.17
Ezetimibe 10 (4.0) 11 (12.6) 0.008
Resins 1 (0.4) 0 (0.0) 1.00
Fibrates 8 (3.2) 6 (6.9) 0.21
Use of antithrombotic agents 27 (10.7) 5 (5.7) 0.21
Antiplatelet agents 22 (8.7) 4 (4.6) 0.25
Anticoagulants 5 (2.0) 1 (1.1) 1.00
Others 0 (0.0) 0 (0.0) –
Data are presented as number (%) of patients or mean ± SD values. HbA1C: glycated hemoglobin; SD: standard deviation; LDL: low- density lipoprotein; HDL: high-density lipoprotein; DPP-4: dipeptidyl peptidase; GLP: glucagon-like peptide-1.
Supplementary Table S2.
Between-group comparison of changes in clinical parameters during the treatment period
Parameters Tofogliflozin group Conventional group P value
Body mass index at baseline (kg/m2) 26.9 ± 62 (n = 127) 26.8 ± 4.6 (n = 125) 0.89 Week 26 (change from baseline) –0.7 ± 0.8 (n = 124)*** –0.1 ± 0.7 (n = 123) < 0.001 Week 52 (change from baseline) –0.8 ± 1.2 (n = 123)*** –0.1 ± 0.9 (n = 119) < 0.001 Week 78 (change from baseline) –0.9 ± 1.4 (n = 118)*** 0.0 ± 1.0 (n = 116) < 0.001 Week 104 (change from baseline) –1.0 ± 1.3 (n = 118)*** –0.3 ± 1.1 (n = 113) < 0.001 Waist circumference at baseline (cm) 91.2 ± 12.3 (n = 119) 91.7 ± 10.7 (n = 117) 0.86
Week 26 (change from baseline) –1.8 ± 6.2 (n = 104)* 1.2 ± 4.4 (n = 99)* <0.001
Week 52 (change from baseline) –0.5 ± 6.3 (n = 105) 1.8 ± 4.8 (n = 105)** 0.004
Week 78 (change from baseline) –0.8 ± 6.8 (n = 101) 1.7 ± 4.4 (n = 96)** 0.003
Week 104 (change from baseline) –1.0 ± 6.2 (n = 104) 1.8 ± 4.3 (n = 98)** <0.001
HbA1c at baseline (%) 7.4 ± 0.7 (n = 127) 7.3 ± 0.7 (n = 125) 0.45
HbA1c at baseline (mmol/mol) 57.0 ± 7.7 (n = 127) 56.2 ± 7.8 (n = 125) 0.45
Week 26 (change from baseline) –3.8 ± 6.3 (n = 125)*** 0.2 ± 5.7 (n = 123) < 0.001 Week 52 (change from baseline) –3.4 ± 7.1 (n = 123)*** 0.2 ± 5.4 (n = 120) <0.001 Week 78 (change from baseline) –3.4 ± 8.3 (n = 117)*** 0.6 ± 8.3 (n = 117) <0.001 Week 104 (change from baseline) –3.3 ± 8.0 (n = 111)*** 0.7 ± 7.4 (n = 111) <0.001 Fasting blood glucose at baseline (mmol/L) 7.8 ± 1.7 (n = 127) 7.9 ± 1.8 (n = 125) 0.55
Week 26 (change from baseline) –0.8 ± 1.7 (n = 121)*** 0.0 ± 2.1 (n = 115) < 0.001
Week 52 (change from baseline) –0.7 ± 1.6 (n = 115)*** 0.0 ± 1.8 (n = 115) 0.003
Week 78 (change from baseline) –0.5 ± 1.7 (n = 112)** 0.1 ± 2. (n = 106) 0.032
Week 104 (change from baseline) –0.7 ± 1.8 (n = 112)*** 0.2 ± 1.8 (n = 109) <0.001
C-peptide at baseline (ng/mL) 1.91 ± 1.24 (n = 127) 1.95 ± 1.04 (n = 125) 0.82
Week 52 (change from baseline) –0.22 ± 0.84 (n= 117)* –0.08 ± 0.87 (n = 116) 0.23
Week 104 (change from baseline) –0.17 ± 0.88 (n= 112)* –0.01 ± 0.88 (n = 108) 0.13 Total cholesterol at baseline (mmol/L) 5.03 ± 0.77 (n = 125) 4.98 ± 0.77 (n = 123) 0.65 Week 26 (change from baseline) 0.08 ± 0.56 (n = 118) –0.05 ± 0.52 (n = 112) 0.06
Week 52 (change from baseline) 0.07 ± 0.56 (n = 120) 0.02 ± 0.57 (n = 118) 0.20
Week 78 (change from baseline) 0.07 ± 0.53 (n = 112) –0.08 ± 0.63 (n = 106) 0.06 Week 104 (change from baseline) 0.07 ± 0.66 (n = 116) –0.04 ± 0.66 (n = 109) 0.20 LDL cholesterol at baseline (mmol/L) 2.96 ± 0.71 (n = 126) 2.95 ± 0.64 (n = 124) 0.96 Week 26 (change from baseline) 0.01 ± 0.54 (n = 122) –0.06 ± 0.49 (n = 120) 0.33 Week 52 (change from baseline) 0.00 ± 0.51 (n = 121) –0.03 ± 0.53 (n = 120) 0.68 Week 78 (change from baseline) 0.02 ± 0.48 (n = 116) –0.10 ± 0.56 (n = 116) 0.07 Week 104 (change from baseline) –0.02 ± 0.63 (n = 117) –0.10 ± 0.58 (n = 111) 0.28 HDL cholesterol at baseline (mmol/L) 1.41 ± 0.37 (n = 127) 1.37 ± 0.32 (n = 125) 0.35
Week 26 (change from baseline) 0.07 ± 0.18 (n = 123) 0.00 ± 0.19 (n = 120) 0.010
Week 52 (change from baseline) 0.06 ± 0.15 (n = 123)* 0.00 ± 0.18 (n = 120) 0.010 Week 78 (change from baseline) 0.06 ± 0.19 (n = 117)** 0.02 ± 0.22 (n = 117) 0.13 Week 104 (change from baseline) 0.06 ± 0.19 (n = 119)** 0.04 ± 0.20 (n = 112)* 0.38 Triglyceride at baseline (mmol/L) 0.22 (–0.08, 0.68) (n = 127) 0.38 (0.04, 0.63) (n = 125) 0.17 Week 26 (change from baseline) –0.04 (–0.26, 0.20) (n = 118) 0.00 (–0.21, 0.23) (n = 113) 0.59 Week 52 (change from baseline) –0.05 (–0.27, 0.16) (n = 114) –0.02 (–0.30, 0.16) (n = 115) 0.53 Week 78 (change from baseline) 0.00 (–0.27, 0.19) (n = 112) –0.04 (–0.26, 0.17) (n = 105) 0.68 Week 104 (change from baseline) –0.05 (–0.25, 0.18) (n = 111) –0.04 (–0.28, 0.22) (n = 108) 0.91
Systolic blood pressure (mmHg) 133.2 ± 14.4 (n = 125) 134.3 ± 17.9 (n = 122) 0.62
Week 26 (change from baseline) –5.0 ± 14.0 (n = 123)* –0.3 ± 16.0 (n = 120) 0.017 Week 52 (change from baseline) –5.7 ± 13.0 (n = 121)*** –2.8 ± 18.2 (n = 117) 0.15 Week 78 (change from baseline) –5.9 ± 14.9 (n = 116)* –1.8 ± 19.6 (n = 112) 0.08 Week 104 (change from baseline) –5.1 ± 16.1 (n = 115)* 0.7 ± 19.2 (n = 110) 0.014
Diastolic blood pressure (mmHg) 77.3 ± 10.5 (n = 125) 78.8 ± 11.2 (n = 122) 0.28
Week 26 (change from baseline) –1.6 ± 8.9 (n = 123)** 0.0 ± 9.1 (n = 120) 0.19 Week 52 (change from baseline) –3.0 ± 10.0 (n = 121)*** –0.5 ± 10.4 (n = 117) 0.16 Week 78 (change from baseline) –2.8 ± 10.0 (n = 116)* –1.0 ± 10.1 (n = 112) 0.42 Week 104 (change from baseline) –3.5 ± 10.4 (n = 115)*** –1.7 ± 10.3 (n = 110) 0.11
eGFR (mL/min/1.73 m2) 81.8 ± 22.1 (n = 126) 82.1 ± 25.9 (n = 124) 0.92
Week 26 (change from baseline) –2.8 ± 9.8 (n = 121)** –3.2 ± 9.8 (n =120)** 0.77 Week 52 (change from baseline) –2.4 ± 10.0 (n = 121)** –2.5 ± 10.0 (n = 119)** 0.96 Week 78 (change from baseline) –3.6 ± 9.9 (n = 117)*** –3.8 ± 10.5 (n = 115)*** 0.88 Week 104 (change from baseline) –3.3 ± 12.8 (n = 118)** –4.8 ± 10.2 (n = 111)*** 0.33 UAE at baseline (mg/g/cre) 2.70(1.84, 3.66) (n = 122) 2.87 (1.67, 4.24) (n = 123) 0.58 Week 26 (change from baseline) –0.08 (–0.61, 0.47) (n = 112) –0.17 (–0.61, 0.37) (n = 107) 0.20 Week 52 (change from baseline) –0.11 (–0.66, 0.36) (n = 116)* 0.03 (–0.37, 0.52) (n = 115) 0.11 Week 78 (change from baseline) –0.05 (–0.53, 0.66) (n = 107) 0.14 (–0.32, 0.87) (n = 104) 0.31 Week 104 (change from baseline) –0.10 (–0.65, 0.34) (n = 114) 0.11 (–0.35, 0.60) (n = 108) 0.025 hsCRP at baseline (ng/mL) 602.0 (308.0, 1460.0) (n = 127) 587.0 (268.0, 1450.0) (n = 125) 0.93
Week 52 (change from baseline) –18.0 (–298.0, 203.0) (n = 119) 10.0 (–257.0, 305.0) (n = 117) 0.50 Week 104 (change from baseline) –41.5 (–428.0, 179.0) (n = 118) 28.5 (–177.0, 343.0) (n = 110) 0.16 Adiponectin at baseline (μg/mL) 7.50 (5.10, 10.30) (n = 127) 7.60 (5.60, 10.40) (n = 125) 0.63 Week 52 (change from baseline) 0.70 (0.10, 1.30) (n = 119)*** 0.30 (–0.30, 1.00) (n = 117)* 0.011 Week 104 (change from baseline) 0.70 (–0.10, 1.80) (n = 118)*** 0.25 (–0.30, 1.10) (n = 110) 0.016 NT-proBNP at baseline (pg/mL) 35.0 (17.0, 66.0) (n = 127) 32.0 (20.0, 62.0) (n = 125) 0.64
Week 52 (change from baseline) –1.0 (–14.0, 13.0) (n = 119) –3.0 (–14.0, 9.0) (n = 117) 0.57 Week 104 (change from baseline) 2.0 (10.0, 18.0) (n = 118) 1.5 (–9.0, 17.0) (n = 110) 0.94 Data are presented as the mean ± SD or median (25th and 75th percentiles) values. Differences in parameters between groups at baseline were analyzed using Student’s t-test or the Wilcoxon rank-sum test. Differences in parameters from baseline to weeks 26, 52, 78, and 104 within each group were analyzed using a one-sample t-test or the Wilcoxon signed-rank test. Differences in parameters from baseline to
weeks 26, 52, 78, and 104 between groups were analyzed using Student’s t-test or the Wilcoxon rank-sum test. *P < 0.05, **P < 0.01, ***P
< 0.001.
eGFR: estimated glomerular filtration rate; SD: standard deviation; UAE: urinary albumin excretion; hs-CRP: high-sensitivity C-reactive protein; NT-proBNP: N-terminal–pro-brain natriuretic peptide; HbA1C:glycated hemoglobin; LDL: low-density lipoprotein; HDL: high- density lipoprotein.
Supplementary Table S3. Changes in concomitantly used anti-diabetic agents
Parameters Tofogliflozin
treatment group
Conventional
treatment group P value Any concomitantly used anti-diabetic agent†
Baseline 112 (88.2) 112 (89.6) 0.84
Week 26 109 (87.2) 115 (92.0) 0.30
Week 52 106 (86.2) 111 (91.7) 0.22
Week 78 103 (85.8) 110 (92.4) 0.14
Week 104 102 (85.7) 105 (92.1) 0.15
Metformin
Baseline 62 (48.8) 70 (56.0) 0.26
Week 26 62 (49.6) 76 (60.8) 0.10
Week 52 59 (48.0) 76 (62.8) 0.021
Week 78 56 (46.7) 75 (63.0) 0.014
Week 104 56 (47.1) 75 (65.8) 0.005
Sulfonylurea
Baseline 31 (24.4) 31 (24.8) 1.00
Week 26 27 (21.6) 31 (24.8) 0.65
Week 52 28 (22.8) 31 (25.6) 0.65
Week 78 27 (22.5) 28 (23.5) 0.88
Week 104 25 (21.0) 29 (25.4) 0.44
Glinides
Baseline 8 (6.3) 8 (6.4) 1.00
Week 26 7 (5.6) 8 (6.4) 1.00
Week 52 6 (4.9) 7 (5.8) 0.78
Week 78 7 (5.8) 8 (6.7) 0.80
Week 104 8 (6.7) 7 (6.1) 1.00
Thiazolidinediones
Baseline 15(11.8) 19 (15.2) 0.47
Week 26 14 (11.2) 19 (15.2) 0.46
Week 52 15 (12.2) 19 (15.7) 0.46
Week 78 14 (11.7) 17 (14.3) 0.57
Week 104 14 (11.8) 16 (14.0) 0.70
α-Glucosidase inhibitors
Baseline 17 (13.4) 16 (12.8) 1.00
Week 26 18 (14.4) 17 (13.6) 1.00
Week 52 18 (14.6) 16 (13.2) 0.85
Week 78 19 (15.8) 16 (13.4) 071
Week 104 18 (15.1) 16 (14.0) 0.85
DPP-4 inhibitors
Baseline 59 (46.5) 74 (59.2) 0.045
Week 26 57 (45.6) 76 (60.8) 0.022
Week 52 57 (46.3) 72 (59.5) 0.041
Week 78 56 (46.7) 71 (59.7) 0.05
Week 104 54 (45.4) 69 (60.5) 0.026
GLP-1 R agonists
Baseline 13 (10.2) 5 (4.0) 0.08
Week 26 13 (10.4) 6 (4.8) 0.15
Week 52 13 (10.6) 7 (5.8) 0.24
Week 78 12 (10.0) 6 (5.0) 0.22
Week 104 12 (10.1) 5 (4.4) 0.13 Insulins
Baseline 28 (22.0) 30 (24.0) 0.77
Week 26 27 (21.6) 30 (24.0) 0.76
Week 52 27 (22.0) 32 (26.4) 0.46
Week 78 25 (20.8) 30 (25.2) 0.45
Week 104 25 (21.0) 28 (24.6) 0.54
Data are presented as the number (%) of patients. The two treatment groups were compared using Fisher’s exact test. †Administration of tofogliflozin in the tofogliflozin treatment group was not considered a concomitant anti-diabetic agent. DPP-4: dipeptidyl peptidase; GLP: glucagon-like peptide-1.
Supplementary Table S4. Changes in concomitantly used cardiovascular medications Tofogliflozin
treatment group
Conventional
treatment group P-value Antihypertensive drugs
Any antihypertensive drugs
Baseline 56 (44.1) 72 (57.6) 0.033
Week 26 55 (44.0) 74 (59.2) 0.023
Week 52 55 (44.7) 73 (60.3) 0.015
Week 78 54 (45.0) 73 (61.3) 0.014
Week 104 54 (45.4) 69 (60.5) 0.026
Angiotensin-converting enzyme inhibitors
Baseline 1 (0.8) 4 (3.2) 0.21
Week 26 1 (0.8) 4 (3.2) 0.37
Week 52 1 (0.8) 4 (3.3) 0.21
Week 78 2 (1.7) 4 (3.4) 0.45
Week 104 2 (1.7) 4 (3.5) 0.44
Angiotensin II receptor blockers
Baseline 48 (37.8) 62 (49.6) 0.08
Week 26 47 (37.6) 64 (51.2) 0.041
Week 52 47 (38.2) 62 (51.2) 0.05
Week 78 45 (37.5) 63 (52.9) 0.019
Week 104 44 (37.0) 59 (51.8) 0.025
Calcium channel blockers
Baseline 35 (27.6) 40 (32.0) 0.49
Week 26 33 (26.4) 41 (32.8) 0.33
Week 52 33 (26.8) 43 (35.5) 0.17
Week 78 32 (26.7) 44 (37.0) 0.10
Week 104 33 (27.7) 42 (36.8) 0.16
Lipid-lowering agents Any lipid-lowering agent
Baseline 53 (41.7) 69 (55.2) 0.043
Week 26 52 (41.6) 69 (55.2) 0.043
Week 52 52 (42.3) 69 (57.0) 0.029
Week 78 55 (45.8) 70 (58.8) 0.09
Week 104 58 (48.7) 69 (60.5) 0.12
Statins
Baseline 48 (37.8) 62 (49.6) 0.08
Week 26 47 (37.6) 62 (49.6) 0.07
Week 52 47 (38.2) 62 (51.2) 0.05
Week 78 49 (40.8) 62 (52.1) 0.09
Week 104 52 (43.7) 62 (54.4) 0.12
Antithrombotic agents Any antithrombotic agent
Baseline 14 (11.0) 13 (10.4) 1.00
Week 26 14 (11.2) 14 (11.2) 1.00
Week 52 15 (12.2) 13 (10.7) 0.84
Week 78 15 (12.5) 14 (11.8) 1.00
Week 104 15 (12.6) 13 (11.4) 0.84
Antiplatelet drugs
Baseline 12 (9.4) 10 (8.0) 0.82
Week 26 12 (9.6) 11 (8.8) 1.00
Week 52 13 (10.6) 10 (8.3) 0.66
Week 78 13 (10.8) 10 (8.4) 0.66
Week 104 13 (10.9) 10 (8.8) 0.66
Anticoagulants
Baseline 2 (1.6) 3 (2.4) 0.68
Week 26 2 (1.6) 3 (2.4) 1.00
Week 52 2 (1.6) 3 (2.5) 0.68
Week 78 2 (1.7) 4 (3.4) 0.45
Week 104 2 (1.7) 3 (2.6) 0.68
Data are presented as number (%) or mean ± standard deviation (SD). The two treatment groups were compared using Fisher’s exact test. SD: standard deviation
Supplementary Table S5. Summary of serious adverse events and adverse events.
Parameters Tofogliflozin treatment
group (n=127) Conventional treatment group (n=125)
Any adverse events 57 (44.9) 67 (53.6)
Severe adverse events 17 (13.4) 22 (17.6)
Death 0 (0) 0 (0)
Worsening of glycemic control 3 (2.4) 10 (8.0)
Hypoglycemia 14 (11.0) 15 (12.0)
Myocardial infarction 1 (0.8) 0 (0)
Other coronary artery diseases 2 (1.6) 1 (0.8)
Stroke 0 (0) 3 (2.4)
Subarachnoid hemorrhage 0 (0) 1 (0.8)
Peripheral artery disease 1 (0.8) 0 (0)
Arrhythmia 2 (1.6) 0 (0)
Venous thrombosis 0 (0) 1 (0.8)
Volume depletion 1 (0.8) 0 (0)
Hepatic cancer 2 (1.6) 0 (0)
Prostate cancer 1 (0.8) 1 (0.8)
Brest cancer 1 (0.8) 2 (1.6)
Malignant lymphoma 1 (0.8) 1 (0.8)
Anemia 0 (0) 1 (0.8)
Vertigo 1 (0.8) 1 (0.8)
ophthalmic diseases 2 (1.6) 5 (4.0)
Otolaryngology disease 5 (3.9) 3 (2.4)
Dental diseases 1 (0.8) 0 (0)
Influenza, common cold 18 (14.2) 15 (12.0)
Pneumonia 0 (0) 2 (1.6)
Other respiratory disease 1 (0.8) 2 (1.6)
Epigastric discomfort 1 (0.8) 1 (0.8)
Digestive tract disease 14 (11.0) 9 (7.2)
Liver dysfunction 1 (0.8) 0 (0)
Renal dysfunction 0 (0) 2 (1.6)
Urinary lithiasis 1 (0.8) 1 (0.8)
Dyslipidemia 0 (0) 1 (0.8)
Thyroid disease 2 (1.6) 1 (0.8)
Urinary tract infection 2 (1.6) 6 (4.8)
Genital infection 1 (0.8) 0 (0)
Genital pruritus 2 (1.6) 0 (0)
Dermatitis 2 (1.6) 0 (0)
Eruption 3 (2.4) 1 (0.8)
Muscle spasm 1 (0.8) 0 (0)
Bone fracture 3 (2.4) 2 (1.6)
Other orthopedic disease 3 (2.4) 9 (7.2)
Edema 0 (0) 1 (0.8)
General fatigue 0 (0) 1 (0.8)
Traumatic injury 0 (0) 3 (2.4)
Others 11 (8.7) 11 (8.8)
Data are presented as number (%) of patients.
Supplementary Table S6. The effect of each treatment on the total score of DTR-QOL7 in the subgroup divided by HbA1c values at Week 104
Total subjects Tofogliflozin
treatment group Conventional
treatment group P-value (inter- treatment
-group) Subjects with
HbA1c < 7 % 8.3 [0.0, 19.4]***
(n=84)
13.9 [0.0, 27.8]***
(n=50)
5.6 [-2.8, 11.1]
(n=34)
0.025 Subjects with
HbA1c with ≥ 7 % 2.8 [-8.3, 13.9]*
(n=115)
8.3 [4.2, 19.4]**
(n=52)
0.0 [-11.1, 8.3]
(n=63)
0.006 P-value
(< 7 % vs. ≥ 7 %)
0.007 0.11 0.09
Data are expressed as the medians [range: 25 % to 75 %]
Change from baseline is shown as the change in the actual value between the baseline and week 104.
Changes from baseline to week 104 were assessed using Wilcoxon’s signed-rank test within the group. *P<0.05, **P<0.01, ***P<0.001.
Differences in delta change in the total score of DTR-QOL7 from baseline to week 104 between the groups (treatment effect) were analyzed using Wilcoxon’s rank sum test.
Supplementary Table S7. Effect of each treatment on the total score of DTR-QOL7 in the subgroup divided by the occurrence of AE
Subjects without AE Subjects with AE
but without SAE Subjects with SAE P-value (inter- group) Tofogliflozin
treatment group
8.3 [0.0, 22.2] ***
(n=55)
13.9 [0.0, 22.2] ***
(n=35)
18.1 [0.0, 25.0]*
(n=12)
0.79
Conventional treatment
group
5.6 [2.8, 11.1]*
(n=44)
-2.8 [-13.9, 8.3]
(n=39)
0.0 [-13.9, 5.6]
(n=15)
0.15
Data are expressed as the medians [range: 25 % to 75 %]
Change from baseline is shown as the change in the actual value between the baseline and week 104.
Changes from baseline to week 104 were assessed using Wilcoxon’s signed-rank test within the group. *P<0.05, **P<0.01, ***P<0.001.
Differences in delta change in the total score of DTR-QOL7 from baseline to week 104 between the groups (treatment effect) were analyzed using Wilcoxon’s rank sum test.
AE: adverse event; SAE: serious adverse event
