Abstract
Aims/Introduction
Tofogliflozin is a potent and highly selective sodium–glucose cotransporter 2 inhibitor, and is currently used to treat patients with type 2 diabetes mellitus. We designed a 3‐year study of tofogliflozin in patients with type 2 diabetes mellitus to evaluate the safety and effectiveness in routine clinical practice. The 3‐ and 12‐month interim analysis showed tofogliflozin was well‐tolerated, safe and clinically effective. Here, we report the results of the 24‐month interim analysis.
Materials and Methods
This is a 3‐year prospective, observational and multicenter post‐marketing study (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term).
Results
Of the 6,897 patients enrolled, 6,712 and 6,461 patients were analyzed for the safety and effectiveness of tofogliflozin, respectively. During the 24‐month observation period, the incidence rates of adverse drug reactions (ADRs) and serious adverse drug reactions were 11.25 and 1.21%, respectively. As to adverse drug reactions of special interest, the incidence rates of hypoglycemia, polyuria/pollakiuria, volume depletion‐related events, urinary tract infections and genital infection were 0.83, 1.28, 1.46, 1.18 and 1.62%, respectively. Renal disorders, and cardiovascular and cerebrovascular disorders occurred in 0.63 and 0.76% of the patients, respectively. Glycated hemoglobin A1c and bodyweight decreased significantly by −0.70% (P < 0.0001) and −2.95 kg (P < 0.0001), respectively, from baseline to week 104 (last observation carried forward).
Conclusions
Significant safety concerns have not been observed, and clinical benefit including a long‐term reduction in glycated hemoglobin A1c over a 104‐week (24 months) observation period with weight loss was suggested in this 24‐month interim analysis of the 3‐year Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term in routine clinical practice.
Keywords: Post‐marketing study, Sodium–glucose transporter 2, Tofogliflozin
Significant safety concerns have not been observed and clinical benefit including a long‐term reduction in glycated hemoglobin A1c over a 104‐week (24 months) observation period with weight loss was suggested in this 24‐month interim analysis of the 3‐year Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term study in routine clinical practice.
Introduction
Tofogliflozin is a potent and highly selective sodium–glucose cotransporter 2 (SGLT2) inhibitor1, 2, 3, and is currently used for the treatment of patients with type 2 diabetes mellitus in Japan4, 5. SGLT2 inhibitors exert their antidiabetic effects by inhibiting SGLT2, which is localized in the proximal renal tubule and is responsible for approximately 90% of glucose reabsorption in the kidney6. Suppression of renal glucose reabsorption and a subsequent increase in urinary glucose excretion results in decreased blood glucose levels7.
In phase III and long‐term clinical trials, once‐daily oral administration of tofogliflozin for 24–52 weeks achieved clinically relevant improvements in glycemic control and weight loss8, 9, 10. In these trials, tofogliflozin was well‐tolerated and most adverse drug reactions (ADRs) were mild or moderate in severity. The common adverse events (AEs) of tofogliflozin observed in the clinical trials were increase in blood ketone body level, hyperketonemia, thirst and pollakiuria, which are known as class effects of SGLT2 inhibitors10. The studies showed that the risk of hypoglycemia was low as long as tofogliflozin was administered as monotherapy8, 9, 10. However, these findings are mainly based on clinical trials that investigated a limited number of patients who met strict eligibility criteria for a duration not exceeding 1 year.
We, therefore, designed a 3‐year post‐marketing study of tofogliflozin in patients with type 2 diabetes mellitus to evaluate the safety and effectiveness in routine clinical practice. The 3‐month11 and 12‐month12 interim analyses showed that tofogliflozin was well‐tolerated, safe and clinically effective. Here, we report the 24‐month results of the interim analysis.
Methods
Study design
The details of the present study have been reported elsewhere12. In brief, this Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational/Long‐Term (J‐STEP/LT) was a prospective, observational and multicenter post‐marketing study co‐sponsored by the manufacturers to evaluate the safety and effectiveness of two tofogliflozin hydrate products, Deberza® 20‐mg tablet (Kowa Company, Ltd., Nagoya, Japan) and Apleway® 20‐mg tablet (Sanofi K.K., Tokyo, Japan). The plan was to carry out the study from September 2014 to May 2019. The study was carried out in accordance with the Japanese regulatory requirements stipulated in the Good Post‐Marketing Study Practice.
Participants and assessment
Tofogliflozin‐naïve patients with type 2 diabetes mellitus were enrolled in this study without limitation in age, glycated hemoglobin (HbA1c), concomitant medications and disease history. The patients were instructed to take tofogliflozin 20 mg once daily before or after breakfast. A central registration system was used, and clinical data recorded in electronic case report forms included demographic and baseline characteristics, details of tofogliflozin treatment, concomitant antidiabetic treatment, clinical course (vital signs, HbA1c, fasting plasma glucose, laboratory tests), and AEs.
Safety was assessed based on the incidences of ADRs and ADRs of special interest, renal disorders, and cardiovascular and cerebrovascular disorders. An ADR was defined as an AE considered to be related to tofogliflozin administration. ADRs of special interest were defined as polyuria/pollakiuria, volume depletion‐related events, urinary tract infection, genital infection, hypoglycemia and skin disorders. ADRs and ADRs of special interest were stratified by patient characteristics and baseline parameters.
Statistical analysis
ADRs were categorized according to the Medical Dictionary for Regulatory Activities/Japanese edition version 21.1. The population for safety analysis was defined as all patients from whom electronic case report forms were collected, excluding those with no follow‐up visits after baseline. The population for effectiveness analysis included all patients for the safety analysis, but those who did not have any efficacy data. Effectiveness was assessed by mean changes ± standard deviation in HbA1c levels and bodyweight. The changes in HbA1c levels and bodyweight were further stratified by baseline estimated glomerular filtration rate (eGFR; <30, 30 to <45, 45 to <60, 60 to <90 or ≥90 mL/min/1.73 m2) and body mass index (BMI; <22, 22 to <25, 25 to <30 or ≥30 kg/m2).
Vital signs and clinical laboratory tests were also assessed and summarized.
The Fisher’s exact test was used to test the associations of the incidence of ADRs with patient characteristics or treatment at baseline. Data at baseline and after treatment were compared using the one‐sample t‐test or Cochran‐Armitage test. The significance level was set at 5%. Missing data at week 104 were imputed with the last observation carried forward (LOCF) method, and the change from baseline to week 104 was calculated using LOCF data. All analyses were carried out using the statistical analysis software (SAS) release 9.4 (SAS Institute Japan Ltd., Tokyo, Japan).
Results
Patient disposition and characteristics
Of the 6,897 patients registered in 1,258 sites, 6,818 electronic case report forms were collected from 1,234 sites. The safety analysis population consisted of 6,712 patients after excluding those who did not return to the site after treatment initiation (n = 42), those ineligible under the criteria (n = 41) and others (n = 23). Of the 6,712 patients, the efficacy analysis population consisted of 6,461 patients after removal of 251 patients for whom no efficacy data were available (Figure 1). In total, 2,212 patients (33.0%) were withdrawn from the study during the 24‐month observation period. Loss to follow up was the most common reason for treatment discontinuation (n = 760; 11.3%), and other reasons included AEs (n = 427; 6.4%), insufficient or no effect (n = 301, 4.5%), patient’s request (n = 330, 4.9%), improvement in diabetes (n = 106, 1.6%) and the convenience of the study site or investigator (n = 176, 2.6%). The mean observation period was 578.0 ± 257.2 days, and the mean number of administration days was 575.3 ± 260.2 days. Patient characteristics are shown in Table 1. Of the 6,712 patients in safety analysis, 60.8% were men. The mean age ± standard deviation was 56.9 ± 12.2 years. The mean BMI was 28.7 ± 5.0 kg/m2. The mean duration of diabetes, baseline HbA1c and eGFR were 8.2 ± 6.4 years, 8.0 ± 1.5% and 82.5 ± 22.5 mL/min/1.73 m2, respectively. Diabetic nephropathy (21.1%), diabetic neuropathy (9.3%) and diabetic retinopathy (8.0%) were reported as diabetes complications. Overall, 80.5% of patients received concomitant antidiabetics, and the most commonly used oral antidiabetic drugs were dipeptidyl peptidase‐4 inhibitors (59.6%), biguanides (45.5%) and sulfonylureas (28.4%). The mean number of oral antidiabetics was 2.0 ± 1.0. Insulin products and glucagon‐like peptide‐1 receptor agonists were used in 11.9 and 5.0% of patients, respectively. Diuretics were used in 448 patients (6.7%; Table 1).
Figure 1.
Patient disposition. eCRF, electronic case report form.
Table 1.
Patients characteristics at baseline (safety analysis population)
| Variables | n | % or mean ± SD |
|---|---|---|
| Total no. patients | 6,712 | 100.0 |
| Sex | ||
| Male | 4,083 | 60.8 |
| Female | 2,629 | 39.2 |
| Age (years) | ||
| Mean ± SD | 6,712 | 56.9 ± 12.2 |
| Duration of diabetes (years) | ||
| Mean ± SD | 3,968 | 8.2 ± 6.4 |
| Bodyweight (kg) | ||
| Mean ± SD | 5,980 | 77.5 ± 16.8 |
| BMI (kg/m2) | ||
| Mean ± SD | 5,538 | 28.7 ± 5.0 |
| eGFR (mL/min/1.73 m2) | ||
| Mean ± SD | 4,950 | 82.5 ± 22.5 |
| HbA1c (%) | ||
| Mean ± SD | 6,411 | 8.0 ± 1.5 |
| Complications | ||
| Diabetic complications | ||
| Yes | 1,884 | 28.1 |
| Diabetic retinopathy | 535 | 8.0 |
| Diabetic nephropathy | 1,415 | 21.1 |
| Diabetic neuropathy | 622 | 9.3 |
| Other | 11 | 0.2 |
| Cardiovascular and cerebrovascular complications | ||
| Yes | 696 | 10.4 |
| Cardiovascular diseases | 558 | 8.3 |
| Cerebrovascular diseases | 159 | 2.4 |
| Cardiac failures | 159 | 2.4 |
| Concomitant antidiabetic treatment | ||
| No | 1,232 | 18.4 |
| Yes | 5,405 | 80.5 |
| Unknown | 75 | 1.1 |
| Oral antidiabetics | ||
| Yes | 5,263 | 78.4 |
| Biguanide | 3,052 | 45.5 |
| Sulfonylurea | 1,903 | 28.4 |
| DPP‐4 inhibitor | 4,001 | 59.6 |
| SGLT2 inhibitor | 1 | 0.01 |
| Rapid‐acting insulin secretagogues | 411 | 6.1 |
| α‐Glucosidase inhibitor | 846 | 12.6 |
| Thiazolidinediones | 958 | 14.3 |
| Other | 1 | 0.01 |
| No. concomitant oral antidiabetics | ||
| Mean ± SD | 5,028 | 2.0 ± 1.0 |
| Insulin products | ||
| Yes | 796 | 11.9 |
| GLP‐1 receptor agonists | ||
| Yes | 333 | 5.0 |
| Concomitant use of diuretics | ||
| Yes | 448 | 6.7 |
BMI, body mass index; DDP‐4, dipeptidyl peptidase‐4; eGFR, estimated glomerular filtration rate; GLP‐1, glucagon‐like peptide‐1; HbA1c, glycated hemoglobin; SD, standard deviation; SGLT2, sodium–glucose cotransporter 2.
Safety
Among 6,712 patients, 952 ADRs occurred in 755 patients (11.25%), and 103 serious ADRs were observed in 81 patients (1.21%) during the 104 weeks (24 months). A total of 659 AE events in 467 patients (6.96%) were determined to have no causal relationship to tofogliflozin use. The incidence of ADRs is shown in Table S1. serious ADRs were observed in 1.21% of patients, including nervous system disorders (17 patients, 0.25%), cardiac disorders (15 patients, 0.22%), and infections and infestations (12 patients, 0.18%). Diabetic ketoacidosis occurred in one patient (0.01%) as a serious ADR. The incidence of ADRs stratified by patient characteristics is shown in Table S2. A total of 12 deaths were reported during this observation period, of which one case (lung cancer) was considered to be related to tofogliflozin, whereas the remaining 11 were deemed to be unrelated to treatment.
Table 2 summarizes the incidence of ADRs of special interest. Hypoglycemia occurred in 56 patients (0.83%), and four patients (0.06%) were serious. Polyuria/pollakiuria (predominantly pollakiuria) occurred in 86 patients (1.28%), none of which was serious. Volume depletion‐related events occurred in 98 patients (1.46%), including dehydration (29, 0.43%), constipation (25, 0.37%), blood urea increased (16, 0.24%), thirst (8, 0.12%) and cerebral infarction (8, 0.12%), as frequently observed ADRs. A total of 16 serious ADRs were reported in this category, which were cerebral infarction (7 patients, 0.10%), myocardial infarction (3 patients, 0.04%) and dehydration (3 patients, 0.04%). Urinary tract infection‐related ADRs included cystitis (40 patients, 0.60%) and urinary tract infection (26 patients, 0.39%), of which acute pyelonephritis (3 patients, 0.04%), urinary tract infection, sepsis shock and pyelonephritis (each 2 patients, 0.03%) were serious. These ADRs were ameliorated after discontinuation of tofogliflozin. Genital infection‐related ADRs included pruritus genital (38 patients, 0.57%), vulvovaginal candidiasis (18 patients, 0.27%) and genital infection (18 patients, 0.27%), none of which was serious. Rash (11 patients, 0.16%) and pruritus (10 patients, 0.15%) were observed as ADRs in skin disorders, of which cellulitis and skin ulcer (each 1 patient, 0.01%) were serious.
Table 2.
Incidence of drug adverse reactions of special interest (safety analysis population)
|
System organ class Preferred term |
All n (%) |
Serious n (%) |
|---|---|---|
| Total no. patients | 6,712 | |
| Hypoglycemia | 56 (0.83) | |
| Hypoglycemia | 56 (0.83) | 4 (0.06) |
| Polyuria/pollakiuria | 86 (1.28) | |
| Nocturia | 13 (0.19) | – |
| Pollakiuria | 64 (0.95) | – |
| Polyuria | 6 (0.09) | – |
| Urine output increased | 3 (0.04) | – |
| Volume depletion‐related events | 98 (1.46) | |
| Blood urea increased | 16 (0.24) | – |
| Cerebral infarction | 8 (0.12) | 7 (0.10) |
| Constipation | 25 (0.37) | – |
| Dehydration | 29 (0.43) | 3 (0.04) |
| Depressed level of consciousness | 1 (0.01) | 1 (0.01) |
| Dry mouth | 1 (0.01) | – |
| Hematocrit increased | 5 | (0.07) |
| Hemoconcentration | 1 (0.01) | – |
| Myocardial infarction | 4 (0.06) | 3 (0.04) |
| Polycythemia | 3 (0.04) | – |
| Thirst | 8 (0.12) | – |
| Heat illness | 2 (0.03) | 1 (0.01) |
| Acute kidney injury | 1 (0.01) | 1 (0.01) |
| Urinary tract infection | 79 (1.18) | |
| Bacteriuria | 1 (0.01) | – |
| Cystitis | 40 (0.60) | 1 (0.01) |
| Pyelonephritis | 2 (0.03) | 2 (0.03) |
| Pyelonephritis acute | 3 (0.04) | 3 (0.04) |
| Sepsis | 1 (0.01) | 1 (0.01) |
| Sepsis shock | 2 (0.03) | 2 (0.03) |
| Urethritis | 5 (0.07) | – |
| Urinary tract infection | 26 (0.39) | 2 (0.03) |
| Cystitis‐like symptom | 2 (0.03) | – |
| Cystitis bacterial | 1 (0.01) | – |
| Genital infection | 109 (1.62) | |
| Balanitis candida | 1 (0.01) | – |
| Balanoposthitis | 9 (0.13) | – |
| Genital candidiasis | 3 (0.04) | – |
| Genital herpes | 1 (0.01) | – |
| Penile ulceration | 1 (0.01) | – |
| Prostatitis | 1 (0.01) | – |
| Pruritus genital | 38 (0.57) | – |
| Vaginal infection | 4 (0.06) | – |
| Vulvitis | 4 (0.06) | – |
| Vulvovaginal candidiasis | 18 (0.27) | – |
| Genital infection | 18 (0.27) | – |
| Vulvovaginal pruritus | 5 (0.07) | – |
| Genital infection female | 1 (0.01) | – |
| Vulvar erosion | 5 (0.07) | – |
| Candida infection | 3 (0.04) | – |
| Skin disorders | 52 (0.77) | |
| Alopecia areata | 1 (0.01) | – |
| Cellulitis | 1 (0.01) | 1 (0.01) |
| Dermatitis | 2 (0.03) | – |
| Drug eruption | 1 (0.01) | – |
| Eczema | 8 (0.12) | – |
| Erythema | 1 (0.01) | – |
| Folliculitis | 1 (0.01) | – |
| Herpes zoster | 2 (0.03) | – |
| Palmoplantar keratoderma | 1 (0.01) | – |
| Pruritus | 10 (0.15) | – |
| Rash | 11 (0.16) | – |
| Rash erythematous | 2 (0.03) | – |
| Rash generalized | 2 (0.03) | – |
| Rash pruritic | 2 (0.03) | – |
| Seborrheic dermatitis | 1 (0.01) | – |
| Skin disorder | 1 (0.01) | – |
| Skin erosion | 1 (0.01) | – |
| Skin infection | 1 (0.01) | – |
| Skin ulcer | 1 (0.01) | 1 (0.01) |
| Tinea pedis | 1 (0.01) | – |
| Urticaria | 1 (0.01) | – |
| Pruritus generalized | 2 (0.03) | – |
| Renal disorders | 42 (0.63) | |
| Albumin urine present | 2 (0.03) | – |
| Azotemia | 1 (0.01) | – |
| Blood creatinine increased | 5 (0.07) | – |
| Blood urea increased | 16 (0.24) | – |
| Glomerular filtration rate decreased | 1 (0.01) | 1 (0.01) |
| Proteinuria | 2 (0.03) | – |
| Renal disorder | 2 (0.03) | – |
| Renal failure | 1 (0.01) | – |
| Protein urine present | 3 (0.04) | – |
| Urine albumin/creatinine ratio increased | 1 (0.01) | – |
| Diabetic nephropathy | 2 (0.03) | 1 (0.01) |
| Urinary sediment abnormal | 1 (0.01) | – |
| Renal impairment | 7 (0.10) | 3 (0.04) |
| Acute kidney injury | 1 (0.01) | 1 (0.01) |
| Cardiovascular and cerebrovascular disorders | 51 (0.76) | |
| Acute myocardial infarction | 7 (0.10) | 7 (0.10) |
| Angina pectoris | 2 (0.03) | 1 (0.01) |
| Angina unstable | 1 (0.01) | 1 (0.01) |
| Arrhythmia | 1 (0.01) | – |
| Atrial fibrillation | 3 (0.04) | 1 (0.01) |
| Brain stem infarction | 1 (0.01) | 1 (0.01) |
| Cardiac failure | 2 (0.03) | 1 (0.01) |
| Cardiac failure congestive | 1 (0.01) | 1 (0.01) |
| Cerebral hemorrhage | 2 (0.03) | 2 (0.03) |
| Cerebral infarction | 8 (0.12) | 7 (0.10) |
| Myocardial infarction | 4 (0.06) | 3 (0.04) |
| Palpitations | 3 (0.04) | – |
| Prinzmetal angina | 1 (0.01) | – |
| Subarachnoid hemorrhage | 1 (0.01) | 1 (0.01) |
| Tachycardia | 9 (0.13) | – |
| Transient ischemic attack | 2 (0.03) | – |
| Ventricular extrasystoles | 1 (0.01) | – |
| Lacunar infarction | 3 (0.04) | 3 (0.04) |
Medical Dictionary for Regulatory Activities/Japanese edition version 21.1.
Incidences of ADRs of special interest were stratified by age, sex and eGFR at baseline. In the age subgroups (≥65 vs <65 years), the incidence of polyuria/pollakiuria (1.79 vs 1.08%) and volume depletion‐related events (2.00 vs 1.25%) were significantly higher in the patients aged ≥65 years than those <65 years (Figure 2a). In the sex subgroups (male vs female), urinary tract infections (0.32 vs 2.51%), genital infections (0.47 vs 3.42%) and skin disorders (0.56 vs 1.10%) occurred more frequently in women than in men, whereas cardiovascular and cerebrovascular disorders (0.98 vs 0.42%) occurred more frequently in men than in women (Figure 2b). In the eGFR subgroups (eGFR of 30 to <45, 45 to <60, 60 to <90 and ≥90 mL/min/1.73 m2), there were significant differences in relation to polyuria/pollakiuria and volume depletion‐related events (Figure 2c).
Figure 2.
Incidences of adverse drug reactions (ADRs) of special interest after 104 weeks of treatment with tofogliflozin, which is stratified by (a) age, (b) sex and (c) eGFR. Fisher’s exact test is performed for (a) and (b), and Cochran‐Armitage test for (c). Number of patients is provided in parentheses. There were no patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2. NS, not significant.
From the population for safety analysis (6,712 patients), cardiovascular and cerebrovascular disorders occurred in 51 patients (0.76%). Cardiovascular disorders that occurred more than twice were tachycardia (9 patients, 0.13%), acute myocardial infarction (7 patients, 0.10%), myocardial infarction (4 patients, 0.06%), atrial fibrillation (3 patients, 0.04%), palpitations (3 patients, 0.04%), angina pectoris (2 patients, 0.03%) and cardiac failure (2 patients, 0.03%). Cerebrovascular disorders that occurred more than twice were cerebral infarction (8 patients, 0.12%), lacunar infarction (3 patients, 0.04%), cerebral hemorrhage (2 patients, 0.03%) and transient ischemic attack (2 patients, 0.03%).
Changes in effectiveness‐related laboratory variables
HbA1c levels (mean ± standard deviation) significantly decreased from 8.00 ± 1.48% (6,238 patients) at baseline to 7.31 ± 1.22% (6,373 patients) at LOCF, with a mean change of −0.70 ± 1.31% (P < 0.0001; Table 3; Figure 3a). A significant reduction in HbA1c level was observed in patients with baseline eGFR of ≥30 mL/min/1.73 m2 (P < 0.0001), but not if eGFR was <30 mL/min/1.73 m2 (Figure S1a). The HbA1c levels significantly decreased irrespective of the baseline BMI (P < 0.0001; Figure S1b). The mean reduction in fasting plasma glucose level was −32.67 ± 62.53 mg/dL (P < 0.0001). Mean bodyweight decreased from 77.84 ± 16.71 kg at baseline (5,385 patients) to 74.88 ± 16.46 kg (5,595 patients) at LOCF, with a mean change of −2.95 ± 4.40 kg (P < 0.0001; Table 3). Bodyweight reduction was higher in higher BMI subgroups, but independent of eGFR except eGFR <30 mL/min/1.73 m2 (Figure S1C), and dependent on increase of BMI (Figure S1D). Changes over time in HbA1c level, fasting plasma glucose level and bodyweight are shown in Figure 3.
Table 3.
Surrogate marker of effectiveness, vital signs and laboratory variables
| Variable | Baseline | Week 24 | Week 52 | Week 104 | LOCF | Mean ± SD (n) | P‐value* |
|---|---|---|---|---|---|---|---|
| Change from baseline to LOCF | |||||||
| HbA1c (%) | 8.00 ± 1.48 (6,238) | 7.22 ± 1.07 (5,037) | 7.14 ± 1.08 (4,903) | 7.19 ± 1.06 (4,260) | 7.31 ± 1.22 (6,373) | −0.70 ± 1.31 (6,170) | <0.0001 |
| FPG (mg/dL) | 170.06 ± 64.88 (3,310) | 134.85 ± 41.27 (2,586) | 134.49 ± 43.49 (2,501) | 134.53 ± 40.97 (2,173) | 137.26 ± 46.32 (4,208) | −32.67 ± 62.53 (3,143) | <0.0001 |
| Bodyweight (kg) | 77.84 ± 16.71 (5,385) | 75.50 ± 16.30 (4,159) | 75.10 ± 16.25 (3,972) | 74.58 ± 15.51 (3,344) | 74.88 ± 16.46 (5,595) | −2.95 ± 4.40 (5,215) | <0.0001 |
| BMI (kg/m2) | 28.85 ± 5.00 (4,959) | 27.98 ± 4.91 (3,824) | 27.78 ± 4.86 (3,654) | 27.58 ± 4.63 (3,045) | 27.79 ± 4.96 (5,059) | −1.10 ± 1.61 (4,806) | <0.0001 |
| Waist circumference (cm) | 96.38 ± 11.58 (943) | 93.48 ± 11.67 (627) | 91.97 ± 11.13 (627) | 92.31 ± 11.39 (514) | 93.44 ± 12.05 (1,142) | −3.01 ± 5.33 (730) | <0.0001 |
| Systolic blood pressure (mmHg) | 132.5 ± 15.6 (5,836) | 128.6 ± 13.8 (4,782) | 128.3 ± 14.2 (4,608) | 128.8 ± 13.6 (4,025) | 128.9 ± 14.4 (6,135) | −3.6 ± 15.7 (5,773) | <0.0001 |
| Diastolic blood pressure (mmHg) | 78.1 ± 11.3 (5,834) | 75.6 ± 10.1 (4,780) | 75.3 ± 10.3 (4,607) | 75.3 ± 9.9 (4,022) | 75.6 ± 10.4 (6,135) | −2.4 ± 10.6 (5,771) | <0.0001 |
| Heart rate (b.p.m.) | 77.5 ± 12.5 (3,529) | 76.0 ± 11.7 (2,963) | 76.1 ± 11.7 (2,846) | 76.3 ± 11.8 (2,496) | 76.8 ± 12.1 (4,059) | −0.9 ± 10.5 (3,429) | <0.0001 |
| Serum creatinine (mg/dL) | 0.73 ± 0.22 (4,821) | 0.75 ± 0.25 (3,777) | 0.76 ± 0.24 (3,746) | 0.75 ± 0.24 (3,232) | 0.76 ± 0.27 (5,457) | 0.02 ± 0.17 (4,587) | <0.0001 |
| eGFR (mL/min/1.73 m2) | 82.44 ± 22.44 (4,821) | 80.97 ± 22.65 (3,777) | 80.39 ± 22.30 (3,746) | 80.48 ± 22.14 (3,232) | 80.68 ± 22.76 (5,457) | −1.99 ± 13.96 (4,587) | <0.0001 |
| Serum albumin (g/dL) | 4.60 ± 4.29 (1,985) | 4.43 ± 1.65 (1,508) | 4.53 ± 2.45 (1,511) | 4.62 ± 4.07 (1,289) | 4.74 ± 5.14 (2,643) | 0.03 ± 3.42 (1,767) | 0.7549 |
| BUN (mg/dL) | 14.86 ± 4.42 (4,049) | 16.27 ± 4.55 (3,143) | 16.14 ± 4.75 (3,118) | 16.29 ± 4.54 (2,625) | 16.26 ± 4.91 (4,726) | 1.40 ± 4.31 (3,815) | <0.0001 |
| AST, U/L (GOT) | 30.74 ± 19.94 (4,826) | 25.11 ± 14.47 (3,636) | 25.54 ± 15.26 (3,598) | 25.42 ± 13.51 (3,124) | 25.63 ± 14.62 (5,439) | −4.81 ± 18.11 (4,546) | <0.0001 |
| ALT, U/L (GPT ) | 38.59 ± 34.96 (4,884) | 29.30 ± 21.45 (3,694) | 29.69 ± 24.10 (3,666) | 29.69 ± 22.11 (3,175) | 30.00 ± 23.72 (5,484) | −8.18 ± 30.79 (4,614) | <0.0001 |
| ALP (IU/L) | 244.91 ± 85.05 (2,520) | 234.02 ± 83.73 (1,949) | 233.11 ± 86.42 (1,895) | 232.47 ± 84.06 (1,577) | 234.56 ± 86.29 (3,163) | −7.88 ± 63.15 (2,271) | <0.0001 |
| γ‐GTP (U/L) | 57.57 ± 68.12 (4,428) | 45.71 ± 60.28 (3,363) | 46.08 ± 66.65 (3,346) | 45.86 ± 69.17 (2,848) | 45.69 ± 64.51 (5,116) | −11.46 ± 55.02 (4,143) | <0.0001 |
| Total bilirubin (mg/dL) | 0.64 ± 0.29 (2,128) | 0.64 ± 0.28 (1,646) | 0.64 ± 0.30 (1,586) | 0.66 ± 0.30 (1,327) | 0.65 ± 0.29 (2,653) | 0.01 ± 0.24 (1,908) | 0.3189 |
| TC (mg/dL) | 196.19 ± 39.39 (3,029) | 195.07 ± 36.35 (2,295) | 192.66 ± 35.38 (2,235) | 192.29 ± 33.85 (1,844) | 193.59 ± 36.73 (3,540) | −2.52 ± 33.21 (2,788) | <0.0001 |
| HDL‐C (mg/dL) | 51.54 ± 13.74 (4,547) | 53.86 ± 14.88 (3,503) | 53.98 ± 14.44 (3,456) | 54.23 ± 14.20 (2,992) | 53.97 ± 14.79 (5,154) | 2.69 ± 9.81 (4,282) | <0.0001 |
| LDL‐C (mg/dL) | 114.25 ± 31.37 (4,526) | 112.28 ± 29.60 (3,486) | 110.56 ± 30.50 (3,497) | 109.28 ± 28.34 (3,064) | 110.91 ± 30.09 (5,192) | −3.44 ± 28.88 (4,277) | <0.0001 |
| non HDL‐C (mg/dL) | 143.94 ± 40.46 (2,724) | 140.43 ± 36.34 (2,078) | 137.76 ± 34.72 (2,034) | 137.85 ± 33.23 (1,700) | 139.18 ± 36.29 (3,149) | −5.20 ± 33.41 (2,451) | <0.0001 |
| TG (mg/dL) | 172.11 ± 149.52 (2,187) | 147.31 ± 106.66 (1,720) | 149.57 ± 101.60 (1,662) | 148.67 ± 98.04 (1,468) | 154.04 ± 131.35 (3,144) | −19.67 ± 104.35 (1,916) | <0.0001 |
| Hemoglobin (g/dL) | 14.85 ± 12.68 (4,063) | 15.60 ± 17.01 (3,129) | 15.37 ± 13.85 (3,098) | 15.53 ± 15.47 (2,682) | 15.45 ± 15.07 (4,924) | 0.49 ± 15.39 (3,809) | 0.0484 |
| Hematocrit (%) | 43.46 ± 4.72 (4,154) | 45.15 ± 4.51 (3,181) | 45.28 ± 4.59 (3,149) | 45.42 ± 4.48 (2,698) | 45.29 ± 4.60 (5,000) | 1.79 ± 3.46 (3,890) | <0.0001 |
| Na (mmol/L) | 139.75 ± 6.99 (2,973) | 140.39 ± 5.42 (2,328) | 140.38 ± 4.77 (2,276) | 140.39 ± 4.00 (1,904) | 140.25 ± 5.08 (3,717) | 0.37 ± 6.48 (2,727) | 0.0028 |
| K (mmol/L) | 4.59 ± 10.35 (3,239) | 4.79 ± 12.24 (2,573) | 4.34 ± 3.93 (2,528) | 4.44 ± 4.77 (2,063) | 4.42 ± 4.40 (4,040) | −0.12 ± 11.63 (2,990) | 0.5656 |
| Cl (mmol/L) | 102.16 ± 4.97 (2,887) | 102.49 ± 6.66 (2,283) | 102.51 ± 7.11 (2,239) | 102.23 ± 7.64 (1,868) | 102.36 ± 7.44 (3,643) | 0.19 ± 7.80 (2,644) | 0.2066 |
| Mg (mg/dL) | 2.73 ± 7.64 (161) | 3.42 ± 10.79 (172) | 3.50 ± 10.94 (171) | 3.31 ± 11.26 (148) | 3.74 ± 12.30 (318) | 0.15 ± 0.59 (141) | 0.0030 |
| Ca (mg/dL) | 9.50 ± 4.62 (819) | 9.42 ± 3.79 (650) | 9.38 ± 3.44 (655) | 14.21 ± 64.40 (541) | 11.57 ± 43.97 (1,163) | 2.23 ± 45.29 (713) | 0.1884 |
| P (mg/dL) | 3.33 ± 0.76 (381) | 4.10 ± 13.02 (320) | 3.38 ± 0.58 (330) | 5.10 ± 20.00 (270) | 4.55 ± 16.40 (603) | 0.09 ± 0.60 (326) | 0.0058 |
| Blood ketone body (μmol/L) | 113.29 ± 131.62 (125) | 139.47 ± 177.01 (117) | 117.24 ± 129.93 (102) | 126.40 ± 161.06 (83) | 144.29 ± 240.16 (233) | 22.26 ± 198.69 (107) | 0.2492 |
| Uric acid (mg/dL) | 5.30 ± 1.36 (3,738) | 5.00 ± 1.27 (2,841) | 5.04 ± 1.31 (2,707) | 5.05 ± 1.23 (2,238) | 5.03 ± 1.27 (4,628) | −0.27 ± 1.04 (3,410) | <0.0001 |
| Serum c‐peptide (ng/mL) | 3.74 ± 5.94 (424) | 3.47 ± 5.13 (231) | 4.74 ± 10.38 (204) | 2.92 ± 2.17 (178) | 4.06 ± 8.27 (579) | −0.10 ± 2.68 (230) | 0.5576 |
One‐sample t‐test. γ‐GTP, γ‐glutamyltranspeptidase; ALP, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartic aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; Ca, calcium; Cl, chlorine; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; GOT, •••; GPT, •••; HbA1c, glycated hemoglobin; HDL‐C, high‐density lipoprotein cholesterol; K, potassium; LDL‐C, low‐density lipoprotein cholesterol; LOCF, last observation carried forward; Mg, magnesium; Na, sodium; P, phosphorus; SD, standard deviation; TC, total cholesterol; TG, triglyceride.
Figure 3.
Changes of (a) glycated hemoglobin (HbA1c; %), (b) fasting plasma glucose (FPG; mg/dL) and (c) bodyweight (kg) from baseline to week 104 (last observation carried forward). Data represent mean ± standard deviation.
Other clinical laboratory variables and vital signs
Changes in other laboratory variables and vital signs are summarized in Table 3. Significant decreases (P < 0.0001) were observed in BMI; waist circumference; systolic blood pressure; diastolic blood pressure; eGFR; liver function parameters, including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and γ‐glutamyl transpeptidase; and lipid parameters, including total cholesterol, low‐density lipoprotein cholesterol, triglyceride and uric acid, whereas significant increases (P < 0.0001) in serum creatinine, blood urea nitrogen, high‐density lipoprotein cholesterol and hematocrit were observed. A significant decrease of eGFR was observed during the observation period.
Discussion
This report presents the results of the 104‐week interim analysis of a 3‐year post‐marketing study of tofogliflozin in patients with type 2 diabetes mellitus to evaluate the safety and effectiveness of tofogliflozin (J‐STEP/LT study). The tolerability, safety and effectiveness of tofogliflozin were maintained at 104‐week treatment, and the results were compared favorably along with the findings from the 3‐month11 and 12‐month12 interim analyses.
The incidences of ADRs and serious ADRs increased slightly from the previous interim analyses: ADRs were 5.14, 9.12 and 11.25%, and serious ADRs were 0.45, 0.88 and 1.21% at 12, 52 and 104 weeks, respectively. The incidences of ADRs of special interest increased in a similar manner. The incidence of cancers was low (0.1%). It has been a concern that SGLT2 inhibitors increase the risk of euglycemic diabetic ketoacidosis, especially in patients with insulin insufficiency13. In the present study, only one patient showed diabetic ketoacidosis. This patient continued to receive tofogliflozin when unwell with acute bronchitis. Whether it was euglycemic was unknown because of a lack of blood glucose level information. However, the risk of diabetic ketoacidosis would be very low in type 2 diabetes mellitus patients receiving tofogliflozin. Although the Canagliflozin Cardiovascular Assessment Study (CANVAS) program has shown that treatment with canagliflozin is associated with an increased risk of lower limb amputation and bone fracture14, these ADRs were not reported in the present patients.
The low risk of hypoglycemia induced by SGLT2 inhibitors is well known because of its insulin‐independent mechanism of action15. In the present study, a total of 56 patients (0.83%) experienced hypoglycemia. Among them, just five patients receiving tofogliflozin as monotherapy experienced hypoglycemia, and most cases of hypoglycemia (51/56 patients) occurred in combination with other classes of antidiabetics, such as insulin products, glucagon‐like peptide‐1 receptor agonists, sulfonyl urease, α‐glucosidase inhibitors and biguanides. Age, sex and eGFR were not found to be factors affecting the incidence of hypoglycemia. Regarding hypoglycemia, four cases were severe; one patient was treated with tofogliflozin and insulin product, and the other three patients received dipeptidyl peptidase‐4 inhibitors, sulfonylureas, thiazolidinedione and/or α‐glycosidase inhibitors as a concomitant antidiabetic. These severe hypoglycemia occurred within the first year, with onset on day 6, 16, 285 and 305 after the start of administration of tofogliflozin, as reported in the previous report of the 12‐month analysis12, but not reported during the observation period from 12 to 24 months. As observed in the present study, polyuria/pollakiuria and volume depletion‐related events are often caused by SGLT2 inhibitors as a class effect due to their mild osmotic diuretic activity6, 16. Among the serious ADRs of special interest, 16 patients experienced volume depletion‐related events, including cerebral infarction (0.10%), dehydration and myocardial infarction (0.04%), depressed level of consciousness, heat illness, and acute kidney injury (each 0.01%). In the present study, these ADRs occurred at a significantly higher rate in the elderly, and it is quite important to guide patients receiving tofogliflozin, particularly the elderly, to ensure sufficient fluid intake17.
Cardiovascular event risk reduction is one of the main goals of diabetic medical management, and it has been well recognized that some SGLT2 inhibitors reduce major adverse cardiovascular events, heart failure hospitalizations and worsening of kidney function independent of glycemic control18, 19. Type 2 diabetes mellitus is frequently comorbid with chronic kidney disease20, and is closely associated with an increased risk of cardiovascular disease18, 21. In the present study, the incidence of renal disorders was low (0.63%), but change in eGFR from baseline to week 104 (LOCF) was ‒1.99 mL/min/1.73 m2 (P < 0.0001). In patients with baseline eGFR ≥90 mL/min/1.73m2, eGFR decline was within the normal range. Conversely, patients with baseline eGFRs of 30–60 mL/min/1.73 m2 showed improved renal function. The previous study showed that tofogliflozin improved albuminuria and renal tubular function in patients with type 2 diabetes mellitus22. These results might represent no major problems with renal dysfunction, which is known to be a common risk for SGLT2 inhibitors indicated in their package inserts, but its renoprotective effect as reported23, 24 in other SGLT2 inhibitors cannot be concluded.
In the present study, the incidence of cardiovascular and cerebrovascular diseases was low (0.76%), with preference to male patients, but half (29/51) of them were serious. History of cardiovascular diseases or renal diseases as a complication are associated with a higher incidence rate. As whether tofogliflozin reduces the risks of cardiovascular and renal outcomes remains to be clarified, further clinical studies are required.
As for effectiveness of tofogliflozin, glycemic control and weight control concerns clinicians as treatment outcomes of type 2 diabetes mellitus. The present analysis showed both improvement of HbA1c (−0.70 ± 1.31%) and weight loss (−2.95 ± 4.40 kg) in people treated with tofogliflozin at week 104 (LOCF), consistent with the results of randomized placebo‐controlled, double‐blind trials9. HbA1c levels were reduced irrespective of BMI, but reduced renal function (eGFR of <30 mL/min/1.73 m2) attenuated the glucose‐lowering effects of tofogliflozin, similar to the clinical findings reported for other SGLT2 inhibitors25.
The weight loss is thought to be caused by a combination of reduced body fat from caloric loss and fluid loss from osmotic diuresis26. Yoshida et al.27 reported that weight loss with tofogliflozin is attenuated as a result of an improved antilipolytic effect of insulin on adipose tissue, which might be a mechanism underlying the slowing of lipolysis progression in the later phase of weight loss. Tofogliflozin improved insulin resistance by increasing glucose uptake, especially in skeletal muscle, and accelerated lipolysis in the adipose tissue of male mice28. There is a concern that tofogliflozin could reduce body fat mass, skeletal muscle mass and skeletal muscle index (a marker of sarcopenia) in patients with type 2 diabetes mellitus29. However, the reduction was small, and their skeletal muscle index (a marker of sarcopenia) remained high enough above the cut‐off values of the Asian sarcopenia criteria30. In the present study, bodyweight was reduced in patients with higher baseline BMI, but was more subtle in lean patients with lower baseline BMI, suggesting tofogliflozin can be used for a wide range of patients.
The present study had several limitations. First, this J‐STEP/LT study is an observational study in routine clinical practice. Unlike randomized controlled trials, a variety of biases are unavoidable. Nevertheless, the data are indispensable in the understanding of actual clinical use and outcomes. Second, we could not determine the safety and efficacy of tofogliflozin because of the lack of a comparator. In particular, the risks/benefits of tofogliflozin associated with cardiovascular disease and renal disorders remain unclear. A placebo‐controlled, long‐term study with a large cohort is required.
In conclusion, the 104‐week (24 months) interim data of our 3‐year post‐marketing study (J‐STEP/LT) show that 24‐month treatment with tofogliflozin is well‐tolerated, safe and effective in Japanese patients with type 2 diabetes mellitus in clinical practice. There were no new clinically significant safety concerns, and clinical benefits including long‐term reduction in HbA1c levels over the 104 weeks along with weight loss, were suggested.
Disclosure
KU received honoraria for lectures from Sanofi and Boehringer Ingelheim, and received scholarship grants from Sumitomo Dainippon Pharma, Ono Pharmaceutical, Terumo, Boehringer Ingelheim, Novo Nordisk Pharma, Kyowa Kirin and Kissei Pharmaceutical. KK is a medical advisor for Sanwa Kagaku Kenkyusho, and received honoraria for lectures from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novo Nordisk Pharma, Ono Pharmaceutical, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma and Taisho Toyama Pharmaceutical, and received scholarship grants from Boehringer Ingelheim, Taisho Toyama Pharmaceutical, Mitsubishi Tanabe Pharma and Kowa Pharmaceutical. SK, SF, YK and RG are employees of Kowa Company, Ltd. MS, RK, HK and MT are employees of Sanofi K. K.
Supporting information
Figure S1 | Changes in glycated hemoglobin (HbA1c) and bodyweight from baseline to week 104 (last observation carried forward).
Table S1 | Incidence of adverse drug reactions (safety analysis population).
Table S2 | Incidence of adverse drug reactions stratified by patient characteristics (safety analysis population).
Acknowledgments
The study was funded by Kowa Company, Ltd. and Sanofi K. K. The authors thank all physicians from 1,258 institutions who participated in this study. The authors thank Dr Tetsuji Asao (SunFlare Co., Ltd.) for writing support. This assistance was funded by Kowa Company, Ltd. and Sanofi K. K.
J Diabetes Investig 2020; 11: 906–916
References
- 1. Ohtake Y, Sato T, Kobayashi T, et al Discovery of tofogliflozin, a novel C‐arylglucoside with an O‐spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 2012; 55: 7828–7840. [DOI] [PubMed] [Google Scholar]
- 2. Suzuki M, Honda K, Fukazawa M, et al Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice. J Pharmacol Exp Ther 2012; 341: 692–701. [DOI] [PubMed] [Google Scholar]
- 3. Rosenwasser RF, Rosenwasser JN, Sutton D, et al Tofogliflozin: a highly selective SGLT2 inhibitor for the treatment of type 2 diabetes. Drugs Today 2014; 50: 739–745. [DOI] [PubMed] [Google Scholar]
- 4. Pafili K, Papanas N. Tofogliflozin: the road goes ever on. Expert Opin Pharmacother 2014; 15: 1197–1201. [DOI] [PubMed] [Google Scholar]
- 5. Poole RM, Prossler JE. Tofogliflozin: first global approval. Drugs 2014; 74: 939–944. [DOI] [PubMed] [Google Scholar]
- 6. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab 2012; 14: 5–14. [DOI] [PubMed] [Google Scholar]
- 7. List JF, Whaley JM. Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans. Kidney Int Suppl 2011; 120: S20–S27. [DOI] [PubMed] [Google Scholar]
- 8. Ikeda S, Takano Y, Cynshi O, et al A novel and selective sodium‐glucose cotransporter‐2 inhibitor, tofogliflozin, improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2015; 17: 984–993. [DOI] [PubMed] [Google Scholar]
- 9. Kaku K, Watada H, Iwamoto Y, et al Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter‐2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo‐controlled, double‐blind, parallel‐group comparative study. Cardiovasc Diabetol 2014; 13: 65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Tanizawa Y, Kaku K, Araki E, et al Long‐term safety and efficacy of tofogliflozin, a selective inhibitor of sodium‐glucose cotransporter 2, as monotherapy or in combination with other oral antidiabetic agents in Japanese patients with type 2 diabetes mellitus: multicenter, open‐label, randomized controlled trials. Expert Opin Pharmacother 2014; 15: 749–766. [DOI] [PubMed] [Google Scholar]
- 11. Utsunomiya K, Senda M, Kakiuchi S, et al Safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus in real‐world clinical practice: Results of 3‐month interim analysis of a long‐term post‐marketing surveillance study (J‐STEP/LT). J Diabetes Investig 2019; 10: 1272–1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Utsunomiya K, Senda M, Kakiuchi S, et al Safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus in real‐world clinical practice: results of 12‐month interim analysis of a long‐term post‐marketing surveillance study (J‐STEP/LT). J Diabetes Investig 2019; 10: 1272–1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig 2016; 7: 135–138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Kaneko M, Narukawa M. Effects of sodium‐glucose cotransporter 2 inhibitors on amputation, bone fracture, and cardiovascular outcomes in patients with type 2 diabetes mellitus using an alternative measure to the hazard ratio. Clin Drug Investig 2019; 39: 179–186. [DOI] [PubMed] [Google Scholar]
- 15. Carlson CJ, Santamarina ML. Update review of the safety of sodium‐glucose cotransporter 2 inhibitors for the treatment of patients with type 2 diabetes mellitus. Expert Opin Drug Saf 2016; 15: 1401–1412. [DOI] [PubMed] [Google Scholar]
- 16. Leiter LA, Langslet G, Vijapurkar U, et al Simultaneous reduction in both HbA1c and body weight with canagliflozin versus glimepiride in patients with type 2 diabetes on metformin. Diabetes Ther 2016; 7: 269–278. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Auersperg EV. Hydration must be maintained in patients taking sodium glucose cotransporter 2 inhibitors. BMJ 2019; 364: I547. [DOI] [PubMed] [Google Scholar]
- 18. Bell DSH, Goncalves E. Heart failure in the patient with diabetes: Epidemiology, aetiology, prognosis, therapy and the effect of glucose‐lowering medications. Diabetes Obes Metab 2019; 21: 1277–1290. [DOI] [PubMed] [Google Scholar]
- 19. Toyama T, Neuen BL, Jun M, et al Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and meta‐analysis. Diabetes Obes Metab 2019; 21: 1237–1250. [DOI] [PubMed] [Google Scholar]
- 20. Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol 2016; 12: 73–81. [DOI] [PubMed] [Google Scholar]
- 21. Pálsson R, Patel UD. Cardiovascular complications of diabetic kidney disease. Adv Chronic Kidney Dis 2014; 21: 273–280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Nunoi K, Sato Y, Kaku K, et al Effects of sodium‐glucose cotransporter 2 inhibitor, tofogliflozin, on the indices of renal tubular function in patients with type 2 diabetes. Endocrinol Diabetes Metab 2018; 1: e00015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Sugiyama S, Jinnouchi H, Yoshida A, et al Renoprotective effects of additional SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus and chronic kidney disease stages 3b–4: a real world report from a Japanese Specialized Diabetes Care Center. J Clin Med Res 2019; 11: 267–274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Davidson JA. SGLT2 inhibitors in patients with type 2 diabetes and renal disease: overview of current evidence. Postgrad Med 2019; 131: 251–260. [DOI] [PubMed] [Google Scholar]
- 25. Scheen AJ. Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease. Clin Pharmacokinet 2015; 54: 691–708. [DOI] [PubMed] [Google Scholar]
- 26. Iwahashi Y, Hirose S, Nakajima S, et al Evaluation of metabolic parameters and body composition in Japanese patients with type 2 diabetes mellitus who were administered tofogliflozin for 48 weeks. Diabetol Int 2017; 8: 205–211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Yoshida A, Matsubayashi Y, Nojima T, et al Attenuation of weight loss through improved antilipolytic effect in adipose tissue via the SGLT2 inhibitor tofogliflozin. J Clin Endocrinol Metab 2019; 104: 3647–3660. [DOI] [PubMed] [Google Scholar]
- 28. Obata A, Kubota N, Kubota T. Tofogliflozin improves insulin resistance in skeletal muscle and accelerates lipolysis in adipose tissue in male mice. Endocrinology 2016; 157: 1029–1042. [DOI] [PubMed] [Google Scholar]
- 29. Kamei S, Iwamoto M, Kameyama M, et al Effect of tofogliflozin on body composition and glycemic control in Japanese subjects with type 2 diabetes mellitus. J Diabetes Res 2018; 2018: 6470137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Chen LK, Liu LK, Woo J, et al Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia. J Am Med Dir Assoc 2014; 15: 95–101. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1 | Changes in glycated hemoglobin (HbA1c) and bodyweight from baseline to week 104 (last observation carried forward).
Table S1 | Incidence of adverse drug reactions (safety analysis population).
Table S2 | Incidence of adverse drug reactions stratified by patient characteristics (safety analysis population).