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Supplementary materialsTablesTable S1. Adverse drug reactions by preferred term that occurred in ≥0.1% patientsSystem organ classThis studyPre-approval clinical trials　Preferred termInfections and infestationsCystitis77(0.70)20(1.20)Nasopharyngitis11(0.10)6(0.36)Periodontitis02(0.12)Pyelonephritis4(0.04)2(0.12)Urethritis2(0.02)2(0.12)Urinary tract infection74(0.67)3(0.18)Vulvitis6(0.05)2(0.12)Vulvovaginal candidiasis31(0.28)17(1.02)Genital infection female24(0.22)0Neoplasms benign, malignant and unspecified (incl cysts and polyps)Colon cancer13(0.12)1(0.06)Blood and lymphatic system disordersAnemia9(0.08)4(0.24)Iron deficiency anemia7(0.06)3(0.18)Metabolism and nutrition disordersDehydration36(0.33)3(0.18)Hypertriglyceridemia23(0.21)0Hypoglycemia48(0.43)9(0.54)Increased appetite4(0.04)3(0.18)Dyslipidemia54(0.49)0Decreased appetite8(0.07)2(0.12)Hyperlipidemia17(0.15)0Psychiatric disordersInsomnia5(0.05)2(0.12)Nervous system disordersCerebral infarction23(0.21)2(0.12)Diabetic neuropathy3(0.03)5(0.30)Dizziness26(0.24)12(0.72)Dizziness postural5(0.05)4(0.24)Headache5(0.05)7(0.42)Hypoesthesia4(0.04)7(0.42)Tremor5(0.05)4(0.24)Eye disordersDiabetic retinopathy2(0.02)6(0.36)Ear and labyrinth disordersVertigo02(0.12)Cardiac disordersAtrial fibrillation6(0.05)2(0.12)Myocardial infarction13(0.12)1(0.06)Ventricular extrasystoles2(0.02)3(0.18)Vascular disordersHypertension53(0.48)5(0.30)Respiratory, thoracic and mediastinal disordersUpper respiratory tract inflammation12(0.11)5(0.30)Gastrointestinal disordersAbdominal distension1(0.01)5(0.30)Abdominal pain2(0.02)2(0.12)Abdominal pain upper9(0.08)5(0.30)Angular cheilitis02(0.12)Chronic gastritis5(0.05)2(0.12)Constipation45(0.41)53(3.18)Dental caries03(0.18)Diarrhea19(0.17)8(0.48)Dyspepsia1(0.01)2(0.12)Feces hard1(0.01)2(0.12)Gastritis4(0.04)3(0.18)Gastroesophageal reflux disease19(0.17)5(0.30)Hemorrhoids02(0.12)Nausea9(0.08)2(0.12)Vomiting2(0.02)2(0.12)Hepatobiliary disordersHepatic function abnormal45(0.41)5(0.30)Hepatic steatosis6(0.05)3(0.18)Liver disorder52(0.47)0Skin and subcutaneous tissue disordersAlopecia1(0.01)2(0.12)Cold sweat1(0.01)4(0.24)Dermatitis1(0.01)2(0.12)Drug eruption44(0.40)3(0.18)Eczema28(0.25)14(0.84)Eczema asteatotic02(0.12)Pruritus42(0.38)3(0.18)Rash23(0.21)9(0.54)Urticaria9(0.08)6(0.36)Musculoskeletal and connective tissue disordersArthritis02(0.12)Muscle spasms6(0.05)3(0.18)Myalgia3(0.03)2(0.12)Renal and urinary disordersDysuria5(0.05)2(0.12)Hematuria2(0.02)2(0.12)Hydronephrosis02(0.12)Hypertonic bladder5(0.05)2(0.12)Nephrolithiasis3(0.03)4(0.24)Nocturia37(0.33)4(0.24)Pollakiuria470(4.25)145(8.69)Polyuria303(2.74)31(1.86)Proteinuria13(0.12)0Renal disorder39(0.35)1(0.06)Urinary incontinence3(0.03)2(0.12)Diabetic nephropathy23(0.21)0Renal impairment49(0.44)0Ureterolithiasis5(0.05)6(0.36)Reproductive system and breast disordersBalanoposthitis14(0.13)0Prostatitis2(0.02)2(0.12)Pruritus genital81(0.73)15(0.90)Vulvovaginal pruritus3(0.03)2(0.12)General disorders and administration site conditionsChest discomfort1(0.01)3(0.18)Feeling abnormal5(0.05)4(0.24)Hunger9(0.08)15(0.90)Malaise17(0.15)9(0.54)Edema peripheral1(0.01)3(0.18)Thirst35(0.32)71(4.25)InvestigationsAlanine aminotransferase increased10(0.09)3(0.18)Albumin urine present27(0.24)0Aspartate aminotransferase increased4(0.04)3(0.18)Beta 2 microglobulin urine increased041(2.46)Beta-N-acetyl-D-glucosaminidase increased05(0.30)Blood creatinine increased12(0.11)3(0.18)Blood potassium increased3(0.03)3(0.18)Blood pressure increased13(0.12)0Blood triglycerides increased49(0.44)0Blood urea increased30(0.27)0Blood uric acid increased13(0.12)3(0.18)Eosinophil count increased02(0.12)Gamma-glutamyltransferase increased19(0.17)0Hematocrit increased21(0.19)1(0.06)Blood urine present1(0.01)5(0.30)Red blood cell count increased5(0.05)2(0.12)Weight decreased40(0.36)39(2.34)White blood cell count increased21(0.19)1(0.06)Protein urine present13(0.12)3(0.18)Urine albumin/creatinine ratio increased4(0.04)12(0.72)Blood ketone body increased14(0.13)4(0.24)Urine ketone body present7(0.06)7(0.42)Bacterial test positive1(0.01)3(0.18)Blood test abnormal02(0.12)　Alpha 1 microglobulin increased08(0.48)No. of patients (%) is shown.Multiple occurrences of the same preferred term events in the same patient were defined as one patient.Coded using MedDRA/J version 22.0.Table S2. Serious adverse drug reactions　　This studyPre-approval clinical trials　　No. of patients with serious ADRs21014Incidence proportion of serious ADRs1.90%0.84%System organ classPreferred termInfections and infestations19(0.17)2(0.12)Encephalitis1(0.01)0Escherichia sepsis1(0.01)0Liver abscess1(0.01)0Penile abscess1(0.01)0Peritonsillar abscess1(0.01)0Pneumonia5(0.05)0Pyelonephritis2(0.02)2(0.12)Pyelonephritis acute3(0.03)0Urinary tract infection3(0.03)0Genital herpes simplex1(0.01)0Escherichia pyelonephritis1(0.01)0Neoplasms benign, malignant and unspecified (including cysts and polyps)46(0.42)3(0.18)Bladder cancer2(0.02)0Breast cancer1(0.01)0Colon cancer12(0.11)1(0.06)Gastric cancer5(0.05)0Metastases to lymph nodes1(0.01)0Pancreatic carcinoma9(0.08)0Pancreatic carcinoma metastatic1(0.01)0Rectal cancer1(0.01)0Renal cancer1(0.01)0Squamous cell carcinoma of skin1(0.01)0Uterine cancer01(0.06)Breast cancer female2(0.02)0Lung neoplasm malignant3(0.03)0Gastric adenoma1(0.01)0Prostate cancer1(0.01)1(0.06)Lung neoplasm1(0.01)0Thyroid cancer3(0.03)0Hepatic cancer1(0.01)0Intraductal proliferative breast lesion1(0.01)0Blood and lymphatic system disorders2(0.02)1(0.06)Anemia1(0.01)0Hemolytic anemia01(0.06)Nephrogenic anemia1(0.01)0Endocrine disorders2(0.02)0Hypothyroidism1(0.01)0Pituitary apoplexy1(0.01)0Metabolism and nutrition disorders12(0.11)0Dehydration4(0.04)0Diabetic ketoacidosis2(0.02)0Hyperglycemia1(0.01)0Hyperphagia1(0.01)0Hypoglycemia3(0.03)0Decreased appetite1(0.01)0Hyperglycemic hyperosmolar nonketotic syndrome1(0.01)0Latent autoimmune diabetes in adults1(0.01)0Psychiatric disorders4(0.04)0Completed suicide1(0.01)0Depression2(0.02)0Suicide attempt1(0.01)0Nervous system disorders37(0.33)1(0.06)Cerebellar infarction1(0.01)0Cerebral artery occlusion1(0.01)0Cerebral hemorrhage2(0.02)0Cerebral infarction18(0.16)1(0.06)Depressed level of consciousness1(0.01)0Dizziness1(0.01)0Lateral medullary syndrome1(0.01)0Somnolence1(0.01)0Subarachnoid hemorrhage1(0.01)0Transient ischemic attack2(0.02)0Lacunar infarction3(0.03)0Putamen hemorrhage1(0.01)0Cerebral artery stenosis1(0.01)0Thalamic infarction1(0.01)0Thrombotic cerebral infarction4(0.04)0Eye disorders3(0.03)0Diabetic retinopathy1(0.01)0Retinal hemorrhage2(0.02)0Ear and labyrinth disorders1(0.01)0Sudden hearing loss1(0.01)0Cardiac disorders45(0.41)2(0.12)Acute myocardial infarction10(0.09)1(0.06)Angina pectoris4(0.04)0Angina unstable6(0.05)1(0.06)Atrial fibrillation2(0.02)0Atrioventricular block1(0.01)0Cardiac failure congestive3(0.03)0Cardio-respiratory arrest1(0.01)0Cardiovascular disorder1(0.01)0Coronary artery disease1(0.01)0Coronary artery occlusion1(0.01)0Myocardial infarction13(0.12)0Ischemic cardiomyopathy1(0.01)0Silent myocardial infarction1(0.01)0Acute coronary syndrome1(0.01)0Congestive cardiomyopathy1(0.01)0Vascular disorders3(0.03)0Hypertension2(0.02)0Varicose vein1(0.01)0Respiratory, thoracic and mediastinal disorders4(0.04)0Hypoxia1(0.01)0Interstitial lung disease1(0.01)0Pneumonitis1(0.01)0Pulmonary infarction1(0.01)0Gastrointestinal disorders6(0.05)1(0.06)Colitis ischemic1(0.01)0Duodenal ulcer1(0.01)0Gastric ulcer hemorrhage1(0.01)0Gastroesophageal reflux disease1(0.01)0Ileus2(0.02)0Pancreatitis acute1(0.01)0Upper gastrointestinal hemorrhage01(0.06)Hepatobiliary disorders10(0.09)0Cholecystitis4(0.04)0Cholecystitis acute1(0.01)0Cholelithiasis2(0.02)0Hepatic cirrhosis2(0.02)0Jaundice cholestatic1(0.01)0Liver disorder1(0.01)0Skin and subcutaneous tissue disorders4(0.04)0Drug eruption1(0.01)0Eczema1(0.01)0Skin ulcer1(0.01)0Urticaria1(0.01)0Musculoskeletal and connective tissue disorders2(0.02)0Osteonecrosis1(0.01)0Rheumatoid arthritis1(0.01)0Renal and urinary disorders9(0.08)3(0.18)Hematuria1(0.01)0Nephrolithiasis01(0.06)Neurogenic bladder1(0.01)0Renal disorder2(0.02)1(0.06)Renal vessel disorder1(0.01)0Diabetic nephropathy1(0.01)0Renal impairment1(0.01)0Chronic kidney disease1(0.01)0Ureterolithiasis1(0.01)1(0.06)Reproductive system and breast disorders2(0.02)0Endometrial hyperplasia1(0.01)0Prostatitis1(0.01)0General disorders and administration site conditions3(0.03)2(0.12)Death01(0.06)Pain01(0.06)Sudden death1(0.01)0Thirst1(0.01)0Sudden cardiac death1(0.01)0Investigations6(0.05)0Blood glucose increased1(0.01)0Blood triglycerides increased1(0.01)0Gamma-glutamyltransferase increased1(0.01)0Hematocrit increased1(0.01)0Weight decreased1(0.01)0Blood ketone body increased1(0.01)0Injury, poisoning and procedural complications5(0.05)0Facial bones fracture1(0.01)0Fall1(0.01)0Femoral neck fracture1(0.01)0Foot fracture1(0.01)0Ligament sprain1(0.01)0Road traffic accident1(0.01)0Subdural hematoma1(0.01)0Contusion1(0.01)0Brain contusion1(0.01)0Surgical and medical procedures1(0.01)0Dialysis1(0.01)0Social circumstances1(0.01)0　Diet noncompliance1(0.01)0Abbreviation: ADRs, adverse drug reactionsNo. of patients (%) is shown.Coded using MedDRA/J version 22.0Table S3. Summary of ADRs of special interest and serious ADRs associated with ADRs of special interest by preferred term reported during the survey period System organ classADRs, n (%)Serious ADRs, n (%)Preferred termPolyuria/PollakiuriaInfections and infestations2 (0.02)0Cystitis1 (0.01)0Urinary tract infection1 (0.01)0Genital infection1 (0.01)0Metabolism and nutrition disorders5 (0.05)0Dehydration1 (0.01)0Polydipsia4 (0.04)0Psychiatric disorders1 (0.01)0Insomnia1 (0.01)0Nervous system disorders3 (0.03)1 (0.01)Dizziness 3 (0.03)1 (0.01)Renal and urinary disorders601 (5.44)0Hypertonic bladder4 (0.04)0Nocturia37 (0.33)0Pollakiuria470 (4.25)0Polyuria303 (2.74)0Urinary incontinence2 (0.02)0Urinary retention1 (0.01)0Cystitis-like symptom1 (0.01)0Reproductive system and breast disorders1 (0.01)0Benign prostatic hyperplasia1 (0.01)0General disorders and administration site conditions5 (0.05)1 (0.01)Thirst5 (0.05)1 (0.01)Investigations5 (0.05)0Urine output increased5 (0.05)0Volume-depletion related events, including dehydrationInfections and infestations7 (0.06)0Cystitis4 (0.04)0Urinary tract infection2 (0.02)0Candida infection1 (0.01)0Blood and lymphatic system disorders2 (0.02)0Polycythemia2 (0.02)0Metabolism and nutrition disorders 47 (0.43)5 (0.05)Dehydration 36 (0.33)4 (0.04)Diabetic ketoacidosis2 (0.02)1 (0.01)Diabetic ketosis1 (0.01)0Hyperkalemia1 (0.01)0Hyperuricemia1 (0.01)0Hypoglycemia4 (0.04)0Hyponatremia1 (0.01)0Ketosis1 (0.01)0Polydipsia2 (0.02)0Decreased appetite1 (0.01)0Hyperglycemic hyperosmolar nonketotic syndrome1 (0.01)1 (0.01)Nervous system disorders12 (0.11)6 (0.05)Cerebral infarction4 (0.04)3 (0.03)Dizziness2 (0.02)1 (0.01)Dizziness exertional1 (0.01)0Dizziness postural2 (0.02)0Headache1 (0.01)0Lacunar infarction1 (0.01)1 (0.01)Thrombotic cerebral infarction1 (0.01)1 (0.01)Eye disorders1 (0.01)0Eyelid edema1 (0.01)0Cardiac disorders5 (0.05)3 (0.03)Acute myocardial infarction1 (0.01)1 (0.01)Angina unstable1 (0.01)1 (0.01)Atrial fibrillation1 (0.01)0Cardiac failure1 (0.01)0Silent myocardial infarction1 (0.01)1 (0.01)Sinus node dysfunction1 (0.01)0Vascular disorders5 (0.05)0Hypotension2 (0.02)0Orthostatic hypotension3 (0.03)0Respiratory, thoracic and mediastinal disorders1 (0.01)0Oropharyngeal pain1 (0.01)0Gastrointestinal disorders20 (0.18)0Constipation17 (0.15)0Diarrhea1 (0.01)0Dry mouth1 (0.01)0Nausea1 (0.01)0Vomiting1 (0.01)0Skin and subcutaneous tissue disorders8 (0.07)1 (0.01)Drug eruption2 (0.02)0Dry skin4 (0.04)0Pruritus1 (0.01)0Skin ulcer1 (0.01)1 (0.01)Musculoskeletal and connective tissue disorders2 (0.02)0Muscle spasms2 (0.02)0Renal and urinary disorders78 (0.71)1 (0.01)Nephrosclerosis1 (0.01)0Nocturia3 (0.03)0Pollakiuria28 (0.25)0Polyuria16 (0.14)0Renal disorder18 (0.16)1 (0.01)Diabetic nephropathy1 (0.01)0Renal impairment19 (0.17)0Chronic kidney disease1 (0.01)0Reproductive system and breast disorders3 (0.03)0Pruritus genital3 (0.03)0General disorders and administration site conditions22 (0.20)1 (0.01)Chest pain2 (0.02)0Fatigue1 (0.01)0Malaise2 (0.02)0Thirst17 (0.15)1 (0.01)Investigations59 (0.53)0Albumin urine present1 (0.01)0Blood creatinine increased5 (0.05)0Blood pressure decreased5 (0.05)0Blood sodium decreased1 (0.01)0Blood triglycerides increased1 (0.01)0Blood urea increased12 (0.11)0Blood uric acid increased2 (0.02)0Glomerular filtration rate decreased3 (0.03)0Hematocrit increased14 (0.13)0Hemoglobin increased3 (0.03)0Low density lipoprotein decreased1 (0.01)0Red blood cell count increased4 (0.04)0Weight decreased12 (0.11)0White blood cell count increased1 (0.01)0Blood ketone body increased2 (0.02)0Urine ketone body present1 (0.01)0Injury, poisoning and procedural complications4 (0.04)0Fall1 (0.01)0Heat illness3 (0.03)0Skin complicationsSkin and subcutaneous tissue disorders164 (1.48)4 (0.04)Dermatitis1 (0.01)0Dermatitis contact1 (0.01)0Drug eruption43 (0.39)1 (0.01)Dry skin4 (0.04)0Eczema27 (0.24)1 (0.01)Erythema3 (0.03)0Fixed eruption1 (0.01)0Keloid scar1 (0.01)0Neurodermatitis1 (0.01)0Prurigo1 (0.01)0Pruritus40 (0.36)0Rash23 (0.21)0Rash generalized5 (0.05)0Rash pruritic3 (0.03)0Skin ulcer1 (0.01)1 (0.01)Urticaria9 (0.08)1 (0.01)Urticaria chronic1 (0.01)0Pruritus generalized4 (0.04)0Pigmentation disorder1 (0.01)0Reproductive system and breast disorders35 (0.32)0Genital rash1 (0.01)0Pruritus genital33 (0.30)0Perineal erythema1 (0.01)0Renal disorderInfections and infestations1 (0.01)1 (0.01)Pyelonephritis1 (0.01)1 (0.01)Blood and lymphatic system disorders1 (0.01)1 (0.01)Nephrogenic anemia1 (0.01)1 (0.01)Metabolism and nutrition disorders3 (0.03)0Dehydration1 (0.01)0Hyperkalemia1 (0.01)0Hypercreatininemia1 (0.01)0Renal and urinary disorders128 (1.16)6 (0.05)Albuminuria1 (0.01)0Hematuria1 (0.01)0Nephrolithiasis1 (0.01)0Nephropathy1 (0.01)0Nephrosclerosis1 (0.01)0Proteinuria11 (0.10)0Renal cyst1 (0.01)0Renal disorder39 (0.35)2 (0.02)Renal vessel disorder1 (0.01)1 (0.01)Diabetic nephropathy23 (0.21)1 (0.01)Renal impairment49 (0.44)1 (0.01)Chronic kidney disease4 (0.04)1 (0.01)Investigations62 (0.56)0Albumin urine2 (0.02)0Albumin urine present18 (0.16)0Blood creatinine increased10 (0.09)0Blood urea increased18 (0.16)0Glomerular filtration rate1 (0.01)0Glomerular filtration rate decreased8 (0.07)0Protein urine present8 (0.07)0Urine albumin/creatinine ratio increased1 (0.01)0Surgical and medical procedures1 (0.01)1 (0.01)Dialysis1 (0.01)1 (0.01)Urinary tract infectionInfections and infestations160 (1.45)9 (0.08)Bacteriuria1 (0.01)0Cystitis77 (0.70)0Cystitis Escherichia1 (0.01)0Pyelitis1 (0.01)0Pyelonephritis4 (0.04)2 (0.02)Pyelonephritis acute4 (0.04)3 (0.03)Urethritis2 (0.02)0Urinary tract infection74 (0.67)3 (0.03)Escherichia pyelonephritis1 (0.01)1 (0.01)Skin and subcutaneous tissue disorders2 (0.02)0Pruritus2 (0.02)0Renal and urinary disorders5 (0.05)0Dysuria3 (0.03)0Urine abnormality1 (0.01)0Cystitis-like symptom1 (0.01)0Investigations5 (0.05)0White blood cells urine positive5 (0.05)0Bacterial test positive1 (0.01)0Genital infectionInfections and infestations91 (0.82)2 (0.02)Balanitis candida2 (0.02)0Epididymitis1 (0.01)0Fungal infection1 (0.01)0Genital candidiasis3 (0.03)0Genital herpes1 (0.01)0Penile abscess1 (0.01)1 (0.01)Tinea cruris1 (0.01)0Vaginal infection5 (0.05)0Vulvitis6 (0.05)0Vulvovaginal candidiasis31 (0.28)0Genital infection2 (0.02)0Skin candida1 (0.01)0Genital infection female24 (0.22)0Genital infection male5 (0.05)0Vulvovaginal mycotic infection1 (0.01)0Genital herpes simplex1 (0.01)1 (0.01)Candida infection6 (0.05)0Bacterial vulvovaginitis1 (0.01)0Neoplasms benign, malignant and unspecified (incl cysts and polyps)1 (0.01)0Anogenital warts1 (0.01)0Skin and subcutaneous tissue disorders4 (0.04)0Eczema1 (0.01)0Erythema1 (0.01)0Pruritus2 (0.02)0Reproductive system and breast disorders69 (0.62)1 (0.01)Balanoposthitis14 (0.13)0Prostatitis1 (0.01)1 (0.01)Pruritus genital47 (0.43)0Vulvovaginal discomfort1 (0.01)0Vulvovaginal pruritus3 (0.03)0Vulvar erosion4 (0.04)0Hepatic disorderInfections and infestations1 (0.01)1 (0.01)Liver abscess1 (0.01)1 (0.01)Neoplasms benign, malignant and unspecified (incl cysts and polyps)1 (0.01)1 (0.01)Colon cancer1 (0.01)1 (0.01)Hepatobiliary disorders104 (0.94)3 (0.03)Hepatic cirrhosis2 (0.02)2 (0.02)Hepatic function abnormal45 (0.41)0Hepatic steatosis5 (0.05)0Hepatitis1 (0.01)0Liver disorder52 (0.47)1 (0.01)Drug-induced liver injury1 (0.01)0Investigations30 (0.27)1 (0.01)Alanine aminotransferase increased9 (0.08)0Aspartate aminotransferase increased4 (0.04)0Blood bilirubin increased1 (0.01)0Gamma-glutamyltransferase abnormal1 (0.01)0Gamma-glutamyltransferase increased15 (0.14)1 (0.01)Blood alkaline phosphatase increased1 (0.01)0Hepatic enzyme increased2 (0.02)0Urobilinogen urine increased1 (0.01)0Liver function test increased 3 (0.03)0Cardiovascular diseaseCardiac disorders59 (0.53)44 (0.40)Acute myocardial infarction10 (0.09)10 (0.09)Angina pectoris9 (0.08)4 (0.04)Angina unstable6 (0.05)6 (0.05)Atrial fibrillation6 (0.05)2 (0.02)Atrioventricular block1 (0.01)1 (0.01)Atrioventricular block first degree1 (0.01)0Bundle branch block right1 (0.01)0Cardiac failure1 (0.01)0Cardiac failure chronic2 (0.02)0Cardiac failure congestive5 (0.05)3 (0.03)Cardio-respiratory arrest1 (0.01)1 (0.01)Cardiovascular disorder1 (0.01)1 (0.01)Coronary artery disease1 (0.01)1 (0.01)Coronary artery occlusion1 (0.01)1 (0.01)Myocardial infarction13 (0.12)13 (0.12)Ventricular extrasystoles2 (0.02)0Ischaemic cardiomyopathy1 (0.01)1 (0.01)Silent myocardial infarction1 (0.01)1 (0.01)Acute coronary syndrome1 (0.01)1 (0.01)Sinus node dysfunction1 (0.01)0Vascular disorders4 (0.04)0Diastolic hypertension1 (0.01)0Hypertension2 (0.02)0Peripheral arterial occlusive disease1 (0.01)0Respiratory, thoracic and mediastinal disorders1 (0.01)1 (0.01)Pulmonary infarction1 (0.01)1 (0.01)General disorders and administration site conditions2 (0.02)1 (0.01)Chest pain1 (0.01)0Sudden cardiac death1 (0.01)1 (0.01)Investigations2 (0.02)0Blood pressure increased1 (0.01)0Electrocardiogram Q wave abnormal1 (0.01)0HypoglycemiaInfections and infestations1 (0.01)0Urinary tract infection1 (0.01)0Metabolism and nutrition disorders48 (0.43)3 (0.03)Hypoglycemia 48 (0.43)3 (0.03)Nervous system disorders3 (0.03)1 (0.01)Depressed level of consciousness1 (0.01)1 (0.01)Tremor2 (0.02)0Eye disorders1 (0.01)0Visual impairment1 (0.01)0Skin and subcutaneous tissue disorders1 (0.01)0Cold sweat1 (0.01)0Renal and urinary disorders1 (0.01)0Pollakiuria1 (0.01)0General disorders and administration site reactions4 (0.04)0Asthenia2 (0.02)0Hunger1 (0.01)0Thirst1 (0.01)0Investigations1 (0.01)0Blood glucose decreased1 (0.01)0Injury, poisoning and procedural complications1 (0.01)0Fall1 (0.01)0Malignant tumorNeoplasms benign, malignant and unspecified (incl cysts and polyps)51 (0.46)44 (0.40)Bladder cancer2 (0.02)2 (0.02)Breast cancer1 (0.01)1 (0.01)Colon cancer13 (0.12)12 (0.11)Gastric cancer5 (0.05)5 (0.05)Metastases to lymph nodes1 (0.01)1 (0.01)Pancreatic carcinoma10 (0.09)9 (0.08)Pancreatic carcinoma metastatic1 (0.01)1 (0.01)Rectal cancer1 (0.01)1 (0.01)Renal cancer1 (0.01)1 (0.01)Squamous cell carcinoma of skin1 (0.01)1 (0.01)Breast cancer female3 (0.03)2 (0.02)Lung neoplasm malignant4 (0.04)3 (0.03)Prostate cancer4 (0.04)1 (0.01)Thyroid cancer3 (0.03)3 (0.03)Hepatic cancer1 (0.01)1 (0.01)Intraductal proliferative breast lesion1 (0.01)1 (0.01)Cerebrovascular diseaseEndocrine disorders1 (0.01)1 (0.01)Pituitary apoplexy1 (0.01)1 (0.01)Nervous system disorders45 (0.41)34 (0.31)Cerebellar infarction1 (0.01)1 (0.01)Cerebral artery occlusion1 (0.01)1 (0.01)Cerebral hemorrhage2 (0.02)2 (0.02)Cerebral infarction23 (0.21)18 (0.16)Lateral medullary syndrome1 (0.01)1 (0.01)Subarachnoid hemorrhage1 (0.01)1 (0.01)Transient ischemic attack7 (0.06)2 (0.02)Lacunar infarction4 (0.04)3 (0.03)Putamen hemorrhage1 (0.01)1 (0.01)Cerebral artery stenosis1 (0.01)1 (0.01)Thalamic infarction1 (0.01)1 (0.01)Thrombotic cerebral infarction4 (0.04)4 (0.04)Injury, poisoning and procedural complications2 (0.02)2 (0.02)Subdural hematoma1 (0.01)1 (0.01)Brain contusion1 (0.01)1 (0.01)Ketoacidosis, events related to ketone-body increaseMetabolism and nutrition disorders7 (0.06)2 (0.02)Diabetic ketoacidosis5 (0.05)2 (0.02)Diabetic ketosis1 (0.01)0Ketosis1 (0.01)0FractureInjury, poisoning and procedural complications4 (0.04)2 (0.02)Ankle fracture1 (0.01)0Facial bones fracture1 (0.01)1 (0.01)Femoral neck fracture1 (0.01)1 (0.01)Foot fracture1 (0.01)1 (0.01)Sternal fracture1 (0.01)0Abbreviation: ADRs, adverse drug reactionsNo. of patients (%) is shown. Coded using MedDRA/J version 22.0Table S4. The time to onset of adverse drug reactions of special interest　<7 days7 to <15 days15 to <30 days30 to <45 days45 to <60 days60 to <90 days90 to <180 days180 to <270 days270 to <360 days360 to <720 days720 to <1080 days≥1080 daysUnknownAll ADRs (3,130 events)456 (14.6)213 (6.8)316 (10.1)198 (6.3)100 (3.2)180 (5.8)327 (10.4)207 (6.6)183 (5.8)446 (14.2)391 (12.5)69 (2.2)44 (1.4)ADRs of special interestsHypoglycemia (61 events)7 (11.5)6 (9.8)3 (4.9)2 (3.3)3 (4.9)7 (11.5)4 (6.6)4 (6.6)5 (8.2)14 (23.0)6 (9.8)00Genital infection (168 events)14 (8.3)15 (8.9)22 (13.1)10 (6.0)9 (5.4)17 (10.1)23 (13.7)17 (10.1)11 (6.5)19 (11.3)8 (4.8)03 (1.8)Urinary tract infection (178 events) 3 (1.7)9 (5.1)23 (12.9)4 (2.2)7 (3.9)16 (9.0)30 (16.9)15 (8.4)10 (5.6)34 (19.1)22 (12.4)4 (2.2)1 (0.6)Polyuria/pollakiuria (841 events)326 (38.8)96 (11.4)143 (17.0)86 (10.2)29 (3.4)27 (3.2)47 (5.6)17 (2.0)12 (1.4)35 (4.2)15 (1.8)08 (1.0)Volume depletion-related events, including dehydration (300 events)33 (11.0)7 (2.3)40 (13.3)29 (9.7)8 (2.7)26 (8.7)47 (15.7)20 (6.7)13 (4.3)46 (15.3)18 (6.0)4 (1.3)9 (3.0)Renal disorder (205 events)1 (0.5)5 (2.4)17 (8.3)11 (5.4)7 (3.4)17 (8.3)29 (14.1)17 (8.3)12 (5.9)36 (17.6)37 (18.0)12 (5.9)4 (2.0)Hepatic disorder (145 events)3 (2.1)1 (0.7)11 (7.6)10 (6.9)6 (4.1)8 (5.5)21 (14.5)10 (6.9)7 (4.8)23 (15.9)32 (22.1)11 (7.6)2 (1.4)Fracture (5 events)000001 (20.0)01 (20.0)1 (20.0)1 (20.0)1 (20.0)00Malignant tumor (52 events)000001 (1.9)6 (11.5)7 (13.5)3 (5.8)19 (36.5)11 (21.2)05 (9.6)Cardiovascular disease (74 events)1 (1.4)03 (4.1)1 (1.4)4 (5.4)3 (4.1)4 (5.4)6 (8.1)8 (10.8)20 (27.0)22 (29.7)1 (1.4)1 (1.4)Cerebrovascular disease (50 events)02 (4.0)01 (2.0)1 (2.0)3 (6.0)5 (10.0)4 (8.0)5 (10.0)22 (44.0)7 (14.0)00Skin complications (205 events)48 (23.4)31 (15.1)18 (8.8)5 (2.4)9 (4.4)16 (7.8)23 (11.2)11 (5.4)7 (3.4)25 (12.2)10 (4.9)02 (1.0)Ketoacidosis, events related to ketone-body increase (7 events)001 (14.3)00001 (14.3)1 (14.3)04 (57.1)00Abbreviation: ADRs, adverse drug reactionsNo. of events (%) is shown.Table S5. Adverse drug reactions of special interest according to the treatment status　Ipragliflozin treatment statusContinuedDose reductionInterruption or discontinuation due to the eventsInterruption or discontinuation for other reasonsCompletion of treatment before occurrence of ADRsUnknownAll ADRs (n = 2,129)1,331(62.52)32(1.50)797(37.44)93(4.37)23(1.08)21(0.99)ADRs of special interestsHypoglycemia (n = 57)27(47.37)5(8.77)24(42.11)3(5.26)00Genital infection (n = 161)64(39.75)1(0.62)99(61.49)01(0.62)0Urinary tract infection (n = 170)84(49.41)1(0.59)91(53.53)1(0.59)1(0.59)0Polyuria/pollakiuria (n = 612)426(69.61)11(1.80)159(25.98)23(3.76)00Volume depletion-related events, including dehydration (n = 243)146(60.08)4(1.65)87(35.80)12(4.94)3(1.23)0Renal disorder (n = 191)154(80.63)1(0.52)24(12.57)14(7.33)01(0.52)Hepatic disorder (n = 133)112(84.21)015(11.28)5(3.76)2(1.50)1(0.75)Fracture (n = 4)4(100.00)01(25.00)000Malignant tumor (n = 51)30(58.82)09(17.65)7(13.73)2(3.92)3(5.88)Cardiovascular disease (n = 67)38(56.72)1(1.49)20(29.85)2(2.99)3(4.48)3(4.48)Cerebrovascular disease (n = 48)18(37.50)1(2.08)21(43.75)4(8.33)1(2.08)5(10.42)Skin complications (n = 198)40(20.20)2(1.01)156(78.79)03(1.52)0Ketoacidosis, events related to ketone-body increase (n = 7)3(42.86)04(57.14)000Abbreviation: ADRs, adverse drug reactionNo. of patients (%) is shown.Note: when the same ADRs of special interest occurred multiple times in the same patient and the treatment categories were different, it was counted as one case in each category.Table S6. Outcomes of adverse drug reactions of special interest　Outcome　ResolvedRemissionNot recoveredSequelaeDeathUnknownAll ADRs (3,130 events)1,635(52.2)1,012(32.3)270(8.6)13(0.4)22(0.7)178(5.7)ADRs of special interestHypoglycemia (61 events) 54(88.5)6(9.8)0001(1.6)Genital infection (168 events)117(69.6)42(25.0)4(2.4)005(3.0)Urinary tract infection (178 events)136(76.4)40(22.5)0002(1.1)Polyuria/pollakiuria (841 events)373(44.4)379(45.1)46(5.5)0043(5.1)Volume depletion-related events, including dehydration (300 events)187(62.3)89(29.7)14(4.7)3(1.0)07(2.3)Renal disorder (205 events)87(42.4)54(26.3)42(20.5)0022(10.7)Hepatic disorder (145 events)54(37.2)35(24.1)35(24.1)01(0.7)20(13.8)Fracture (5 events)2(40.0)3(60.0)0000Malignant tumor (52 events)20(38.5)11(21.2)5(9.6)07(13.5)9(17.3)Cardiovascular disease (74 events)29(39.2)26(35.1)4(5.4)06(8.1)9(12.2)Cerebrovascular disease (50 events)17(34.0)15(30.0)1(2.0)12(24.0)1(2.0)4(8.0)Skin complications (205 events)141(68.8)55(26.8)9(4.4)000Ketoacidosis, events related to ketone-body increase (7 events)5(71.4)1(14.3)0001(14.3)Abbreviation: ADRs, adverse drug reactionNo. of events (%) is shown.Table S7. Vital signs and laboratory variables in the safety analysis set　Actual value　Change from baseline　Baseline36 months　1 month3 months6 months12 months24 months36 monthsWaist circumference, cm96.73 ± 12.10 (1,632)92.38 ± 11.77 (865)─1.18 ± 2.64* (817)─1.94 ± 3.28* (1,058)─2.18 ± 3.77* (860)─2.52 ± 4.29* (868)─2.37 ± 4.09* (761)─2.82 ± 4.64* (654)BMI, kg/m229.08 ± 5.30 (7,492)27.85 ± 4.93 (3,998)─0.48 ± 0.59* (5,213)─0.78 ± 0.87* (6,366)─0.91 ± 1.12* (5,262)─1.04 ± 1.34* (4,976)─1.11 ± 1.50* (4,219)─1.24 ± 1.60* (3,689)Heart rate, bpm77.9 ± 12.3 (5,193)76.5 ± 11.5 (3,167)─0.6 ± 8.7* (3,481)─0.8 ± 9.1* (4,269)─0.9 ± 9.4* (3,595)─0.9 ± 9.4* (3,329)─0.8 ± 9.6* (2,883)─0.7 ± 10.1* (2,556)White blood cell count, /μL7041.0 ± 1934.2 (6,010)6752.1 ± 1708.2 (3,572)15.9 ± 1282.5 (3,159)32.4 ± 1304.0 (4,526)25.8 ± 1441.1 (3,851)─103.6 ± 1390.6* (3,719)─173.2 ± 1375.9* (3,198)─237.8 ± 1413.4* (2,821)Red blood cell count, × 104/μL479.0 ± 101.8 (6,009)494.6 ± 50.0 (3,586)4.9 ± 132.9* (3,153)15.4 ± 27.0* (4,545)18.8 ± 28.8* (3,841)17.5 ± 29.9* (3,715)17.2 ± 31.7* (3,200)17.1 ± 32.0* (2,824)Hemoglobin, g/dL14.43 ± 1.52 (5,993)14.95 ± 1.47 (3,590)0.23 ± 0.67* (3,132)0.42 ± 0.78* (4,530)0.50 ± 0.85* (3,844)0.50 ± 0.90* (3,714)0.49 ± 0.98* (3,197)0.50 ± 1.01* (2,833)Hematocrit, %43.18 ± 4.08 (6,028)45.25 ± 4.12 (3,583)0.95 ± 2.09* (3,145)1.62 ± 2.40* (4,546)1.84 ± 2.56* (3,842)1.88 ± 2.66* (3,709)1.88 ± 2.92* (3,192)1.98 ± 3.04* (2,814)Total bilirubin, mg/dL0.632 ± 0.250 (3,152)0.651 ± 0.247 (1,913)0.010 ± 0.190* (1,515)0.006 ± 0.189 (2,287)0.022 ± 0.199* (1,876)0.019 ± 0.201* (1,837)0.023 ± 0.196* (1,591)0.031 ± 0.201* (1,421)BUN, mg/dL14.83 ± 4.51 (5,856)16.08 ± 4.42 (3,462)0.71 ± 3.50* (3,123)0.80 ± 3.62* (4,489)1.04 ± 3.68* (3,775)1.15 ± 3.67* (3,652)1.26 ± 3.81* (3,136)1.29 ± 3.75* (2,752)Serum albumin, g/dL4.32 ± 0.40 (2,992)4.33 ± 0.35 (1,797)0.05 ± 0.24* (1,475)0.04 ± 0.26* (2,202)0.05 ± 0.27* (1,754)0.04 ± 0.29* (1,705)0.02 ± 0.30* (1,437)0.01 ± 0.31 (1,266)Serum creatinine, mg/dL0.738 ± 0.222 (6,763)0.749 ± 0.228 (3,995)0.029 ± 0.086* (3,616)0.018 ± 0.092* (5,295)0.015 ± 0.096* (4,449)0.017 ± 0.100* (4,297)0.018 ± 0.127* (3,664)0.020 ± 0.126* (3,240)Sodium, mmol/L140.1 ± 2.5 (4,733)140.7 ± 2.4 (2,680)0.6 ± 2.3* (2,419)0.4 ± 2.4* (3,529)0.4 ± 2.4* (2,916)0.5 ± 2.4* (2,813)0.4 ± 2.5* (2,382)0.4 ± 2.6* (2,081)Chloride, mmol/L102.6 ± 2.9 (4,613)102.9 ± 2.7 (2,643)0.6 ± 2.6* (2,359)0.4 ± 2.6* (3,448)0.3 ± 2.7* (2,856)0.5 ± 2.6* (2,737)0.3 ± 2.7* (2,325)0.4 ± 2.9* (2,041)Potassium, mmol/L4.22 ± 0.43 (5,040)4.24 ± 0.40 (2,766)─0.02 ± 0.40* (2,649)─0.02 ± 0.42* (3,802)0.04 ± 0.45* (3,157)─0.02 ± 0.39* (3,059)0.00 ± 0.40 (2,476)0.00 ± 0.40 (2,145)Calcium, mmol/L9.34 ± 0.45 (1,501)9.29 ± 0.45 (920)0.04 ± 0.37* (676)0.02 ± 0.36 (1,021)0.01 ± 0.38 (807)─0.03 ± 0.36* (817)─0.05 ± 0.40* (688)─0.04 ± 0.43* (596)Phosphorus, mg/dL3.26 ± 0.66 (795)3.35 ± 0.56 (492)0.16 ± 0.56* (344)0.15 ± 0.52* (524)0.15 ± 0.53* (389)0.12 ± 0.56* (415)0.08 ± 0.48* (337)0.13 ± 0.53* (286)Magnesium, mg/dL2.09 ± 0.24 (262)2.23 ± 0.23 (254)0.09 ± 0.17* (98)0.07 ± 0.18* (140)0.09 ± 0.15* (119)0.08 ± 0.19* (114)0.11 ± 0.20* (88)0.10 ± 0.22* (75)Serum ketone body, μmol/L131.14 ± 138.30 (140)111.45 ± 158.41 (115)27.81 ± 149.82 (80)21.93 ± 148.85 (100)54.83 ± 136.46* (63)25.43 ± 141.33 (56)35.51 ± 130.49 (46)3.81 ± 83.00 (37)Fasting C-peptide, ng/mL3.461 ± 4.245 (374)2.837 ± 1.773 (148)─0.707 ± 6.979 (88)─0.796 ± 5.953 (134)─1.077 ± 6.792 (100)─1.517 ± 7.080* (94)─0.336 ± 1.837 (67)─0.767 ± 1.843* (69)eGFR, mL/min/1.73m281.23 ± 20.14 (6,697)78.62 ± 19.27 (3,979)─3.05 ± 9.10* (3,577)─2.10 ± 9.82* (5,224)─1.82 ± 10.46* (4,393)─2.19 ± 10.73* (4,256)─2.49 ± 11.25* (3,631)─2.90 ± 11.84* (3,211)pH5.98 ± 0.74 (3,850)5.94 ± 0.73 (2,256)─0.18 ± 0.74* (2,536)─0.14 ± 0.77* (3,096)─0.11 ± 0.80* (2,553)─0.12 ± 0.79* (2,324)─0.08 ± 0.83* (1,963)─0.04 ± 0.84* (1,731)Urinary albumin, mg/g?Cre110.22 ± 382.96 (780)77.68 ± 314.59 (437)─23.29 ± 154.99 (133)─9.90 ± 288.04 (334)─41.18 ± 224.33* (291)─19.63 ± 149.39* (312)─15.22 ± 241.29 (256)─26.43 ± 264.49 (217)Urine creatinine, mg/dL109.787 ± 131.435 (622)70.615 ± 53.280 (350)　─19.270 ± 68.580* (232)─19.340 ± 72.229* (344)─29.139 ± 67.673* (268)─28.828 ± 103.601* (263)─25.985 ± 59.226* (198)─24.439 ± 67.315* (162)Abbreviations: BMI, body mass index; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rateMean ± SD (n) are shown. *P < 0.05 vs baseline (one-sample t-test)Table S8. Laboratory variables in the efficacy analysis set　Actual value　Change from baseline　Baseline36 months　1 month3 months6 months12 months24 months36 monthsFasting insulin, μU/mL13.01 ± 9.58 (562)10.57 ± 7.65 (266)─1.51 ± 5.73* (155)─1.48 ± 6.69* (260)─1.45 ± 7.27* (227)─2.61 ± 7.50* (193)─3.55 ± 7.79* (179)─3.05 ± 8.23* (140)SBP, mmHg133.3 ± 15.2 (7,144)129.1 ± 13.1 (4,130)─3.8 ± 13.3* (5,173)─3.8 ± 14.0* (6,281)─3.4 ± 14.6* (5,291)─4.3 ± 14.6* (4,949)─4.1 ± 14.6* (4,225)─4.4 ± 14.7* (3,777)DBP, mmHg78.1 ± 10.4 (7,066)75.6 ± 9.6 (4,110)─1.8 ± 9.1* (5,095)─1.9 ± 9.4* (6,202)─1.6 ± 9.7* (5,210)─2.5 ± 9.7* (4,891)─2.7 ± 9.9* (4,179)─2.7 ± 10.1* (3,732)AST (GOT), U/L30.2 ± 19.4 (5,813)25.4 ± 13.1 (3,346)─1.9 ± 12.2* (3,241)─3.4 ± 14.0* (4,636)─4.5 ± 15.2* (3,966)─4.6 ± 16.3* (3,780)─4.6 ± 15.6* (3,243)─4.2 ± 15.1* (2,875)ALT (GPT), U/L38.2 ± 29.1 (5,882)29.6 ± 20.3 (3,369)─3.2 ± 14.7* (3,268)─5.7 ± 18.7* (4,719)─7.4 ± 20.2* (4,021)─8.0 ± 21.0* (3,849)─8.0 ± 21.4* (3,286)─7.6 ± 21.1* (2,913)ALP, U/L245.2 ± 83.6 (3,150)230.3 ± 70.5 (1,833)─11.8 ± 44.0* (1,583)─8.6 ± 47.9* (2,335)─6.0 ± 52.0* (1,952)─8.2 ± 55.1* (1,871)─10.0 ± 55.3* (1,634)─10.8 ± 55.6* (1,417)γ-GTP, U/L58.7 ± 70.9 (5,422)43.8 ± 51.8 (3,121)─7.9 ± 29.9* (2,979)─9.2 ± 40.0* (4,293)─10.5 ± 40.7* (3,626)─10.8 ± 42.3* (3,477)─11.2 ± 44.0* (3,007)─12.0 ± 45.6* (2,647)Total cholesterol, mg/dL196.7 ± 39.9 (3,721)191.4 ± 35.2 (1,983)─4.8 ± 28.9* (2,006)─1.9 ± 28.6* (2,925)─0.7 ± 30.9 (2,440)─2.4 ± 30.7* (2,288)─2.3 ± 31.5* (1,936)─3.0 ± 32.6* (1,656)LDL-C, mg/dL114.5 ± 31.8 (5,343)109.0 ± 28.2 (3,136)─3.3 ± 23.2* (2,927)─1.7 ± 24.5* (4,223)─2.4 ± 26.0* (3,604)─4.0 ± 26.6* (3,419)─5.3 ± 27.9* (2,936)─5.5 ± 29.4* (2,573)HDL-C, mg/dL50.8 ± 13.6 (5,580)54.3 ± 15.8 (3,221)0.3 ± 7.0* (3,139)1.4 ± 8.3* (4,478)3.1 ± 8.9* (3,835)2.9 ± 9.2* (3,638)3.0 ± 9.8* (3,117)3.2 ± 9.2* (2,737)non-HDL-C, mg/dL143.5 ± 35.1 (3,398)135.6 ± 32.2 (1,833)─4.4 ± 23.9* (1,828)─2.9 ± 25.7* (2,659)─3.5 ± 27.1* (2,218)─4.7 ± 28.6* (2,079)─5.0 ± 30.1* (1,776)─6.2 ± 30.6* (1,521)Triglyceride, mg/dL196.7 ± 183.8 (5,854)173.6 ± 139.2 (3,368)─17.8 ± 155.6* (3,310)─16.6 ± 155.5* (4,703)─18.7 ± 143.2* (4,040)─16.2 ± 143.7* (3,829)─15.7 ± 131.2* (3,296)─14.4 ± 135.3* (2,881)Uric acid, mg/dL5.34 ± 1.32 (5,177)5.06 ± 1.21 (2,994)　─0.35 ± 0.91* (2,797)─0.29 ± 0.90* (4,057)─0.32 ± 0.92* (3,428)─0.29 ± 0.94* (3,276)─0.26 ± 0.98* (2,822)─0.24 ± 1.01* (2,465)Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; γ-GTP, gamma-glutamyltransferase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; non-HDL-C, non-high-density lipoprotein cholesterol; SBP, systolic blood pressureMean ± SD (n) are shown. *P < 0.05 vs baseline (one-sample t-test) ................
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