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Original Research

1.

Introduction

2.

Patients and methods

3.

Results

4.

Discussion

5.

Conclusion

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 Yukio Tanizawa†, Kohei Kaku, Eiichi Araki, Kazuyuki Tobe, Yasuo Terauchi, Kazunori Utsunomiya, Yasuhiko Iwamoto, Hirotaka Watada, Wataru Ohtsuka, Daisuke Watanabe, Hideki Suganami & for the Tofogliflozin 004 and 005 Study group †

Yamaguchi University Graduate School of Medicine, Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Ube, Japan

Objective: To evaluate long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes as monotherapy or in combination with other oral antidiabetic agents, we conducted 52-week, open-label, randomized controlled trials. Research design and methods: The single-agent trial included patients with inadequate glycemic control on diet and exercise, whereas the add-on trial included those uncontrolled with any of the oral antidiabetic agents. In both trials, patients were randomly assigned to receive tofogliflozin 20 or 40 mg once daily orally for 52 weeks. Main outcome measures: Safety assessments. Results: A total of 194 patients (65, 20-mg group; 129, 40-mg group) were enrolled into the single-agent trial, whereas 602 (178 and 424, respectively) were enrolled into the add-on trial. Tofogliflozin was well tolerated for 52 weeks in both trials with < 6% of treatment discontinuation because of adverse events in each treatment group. It also reduced hemoglobin A1c. In the single-agent trial, mean reductions at 52 weeks were 0.67 and 0.66% in the 20- and 40-mg groups, respectively. In the add-on trial, mean reductions ranged from 0.71 to 0.93% across the subgroups by dose and background therapy. Conclusion: Tofogliflozin was well tolerated and showed sustained efficacy in both trials. Keywords: randomized controlled trial, sodium-glucose cotransporter-2 inhibitor, tofogliflozin, type 2 diabetes mellitus Expert Opin. Pharmacother. (2014) 15(6):749-766

10.1517/14656566.2014.887680 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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1.

Introduction

2.

Type 2 diabetes mellitus is one of the most prevalent chronic diseases in the modern world [1]. Although the number of pharmacological treatment options has increased, many patients fail to achieve glycemic goals because of the progressive nature of diabetes [2]. Especially, those receiving antidiabetic agents with insulin-dependent mechanisms of action often fail to maintain glycemic control as b-cell function declines. In addition, the use of these agents can also be limited by adverse reactions such as hypoglycemia or weight gain [3]. Although glucagon-like peptide-1 receptor agonists reduce blood glucose level and body weight with few episodes of severe hypoglycemia [3,4], their injectable forms may not be suitable for all patients who need long-term pharmacological treatment. Under these circumstances, a new class of antidiabetic agents is needed. This need has led to the recent development of the sodiumglucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is a sodium-solute cotransport protein located in the proximal renal tubules that reabsorbs the majority of glomerularfiltered glucose [5,6]. The SGLT2 inhibitors increase renal glucose excretion and reduce blood glucose level by inhibiting SGLT2. Results from the previous clinical trials have shown that the SGLT2 inhibitors are effective in treating patients with type 2 diabetes [7-11]. In addition, their insulinindependent mechanism of action can complement the efficacy of other antidiabetic agents, which suggest the possibility that the SGLT2 inhibitors may be used in combination with existing therapies. Tofogliflozin is a newly developed SGLT2 inhibitor. In the previous nonclinical study, the selectivity of tofogliflozin to human SGLT2 versus SGLT1, SGLT6, and sodium/ myoinositol transporter 1 was the highest among the tested SGLT2 inhibitors under clinical development [12]. Furthermore, tofogliflozin reduced renal glucose reabsorption under hyperglycemic conditions but not under hypoglycemic or euglycemic conditions [13]. These characteristics suggest that the drug may provide efficacy with low risk of hypoglycemia. In our 24-week double-blind, randomized controlled trial, tofogliflozin improved hemoglobin A1c (HbA1c) significantly better than placebo and induced significant weight loss. However, the long-term safety and efficacy of tofogliflozin remain uncertain because the treatment period of that trial was limited to 24 weeks. In addition, the safety and efficacy of tofogliflozin when added to existing background therapies have not been evaluated because that trial included patients whose hyperglycemia was not adequately controlled with diet and exercise alone (without the addition of drug therapy other than tofogliflozin). Thus, we conducted 52-week randomized controlled trials to evaluate the long-term safety and efficacy of tofogliflozin as monotherapy or in combination with other oral antidiabetic agents.

750

Patients and methods

Trial design and ethical considerations The 52-week, multicenter, open-label, randomized controlled trials consisted of a single-agent trial and an add-on trial. Both trials were conducted at Japanese clinics and hospitals in accordance with the Declaration of Helsinki and Good Clinical Practice. The protocols were reviewed and approved by the institutional review board of each participating center. All patients provided written informed consent. 2.1

Eligibility criteria Patients aged at least 20 years with type 2 diabetes and body mass index of 18.5 -- 44.9 kg/m2 were eligible for the singleagent trial if their hyperglycemia was not adequately controlled (HbA1c £ 6.8%) with diet and exercise alone for at least 8 weeks. Upper limit of HbA1c (< 10.3%) was also set to examine the safety and efficacy of glucose-lowering agents appropriately, in general. Patients were eligible for the addon trial if their hyperglycemia was not adequately controlled with one of the following agents in addition to diet and exercise for at least 8 weeks: sulfonylureas, glinides, biguanides, thiazolidinedione (i.e., pioglitazone), a-glucosidase inhibitors, or dipeptidyl peptidase-4 inhibitors. Inclusion criteria of HbA1c were set as in the single-agent trial. Patients were excluded from both trials if they had type 1 diabetes, diabetes resulting from pancreatic injury, or diabetes secondary to Cushing’s syndrome or acromegaly. Other major exclusion criteria were acute diabetic complications such as diabetic ketoacidosis or hyperglycemic hyperosmolar coma; acute coronary disease, stroke, or recurrent genitourinary tract infection; dehydration requiring hospitalization; serum sodium < 130 mEq/l or ‡ 155 mEq/l; severe hypoglycemia or frequently occurring hypoglycemia (more than twice per week); heart failure (New York Heart Association class III or IV); congenital renal glycosuria; signs of gastrointestinal, renal, heamatologic (e.g., hemoglobinopathy or chronic anemia), or urologic disease that would cause difficulties during the studies; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ‡ 2.5  the upper limit of normal; serum creatinine ‡ 2.0 mg/dl for men and ‡ 1.5 mg/dl for women; uncontrolled hypertension (systolic blood pressure ‡ 180 mm Hg or diastolic blood pressure ‡ 110 mm Hg; history of treatment using antiobesity or antidiabetic agents (except for the background therapy in the add-on trial); or history of treatment using corticosteroids expect for topical applications, eye drops, and sprays. Pregnant women and breast-feeding women were also excluded, as were women who had a partner if they did not use adequate contraceptive precautions. 2.2

Treatments Patients were randomly assigned to receive tofogliflozin 20 or 40 mg. Tofogliflozin was administered once daily orally in the 2.3

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Long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus

morning (before or after breakfast in single-agent trial and only before in add-on trial) for 52 weeks. Allocation sequences in both trials were computer-generated by a central randomization facility using the minimization method with balancing factors of HbA1c level (< 8.3 or ‡ 8.3%) and sex. If patient eligibility was confirmed at screening period, the investigator contacted the data center through the interactive web response system and was notified of the allocated dose of tofogliflozin. Diet and exercise were not changed throughout the treatment period. In the add-on trial, the dose of sulfonylurea was reduced if unacceptable hypoglycemia occurred. Other dosing regimens of the background therapies were not changed. Outcome measures During the treatment period, patients visited the institution at 4-week intervals, and treatment compliance was investigated at each visit. Laboratory tests were also performed at each visit. Laboratory variables including HbA1c were analyzed at the central laboratory. The primary outcomes were the safety assessments including adverse events, laboratory variables, vital signs, 12-lead electrocardiogram, and self-monitoring of blood glucose. At each visit, patients were monitored for signs and symptoms of any unfavorable or unintended medical occurrence. Any events with symptoms or signs of low glucose level were treated as hypoglycemia. Severe hypoglycemia was defined as a symptomatic episode in which the patient required external assistance because of impaired consciousness or coma. Mild hypoglycemia was defined as a symptomatic episode, which resolved rapidly with food or glucagon/glucose intake. It also included low blood glucose level (£ 50 mg/dl) without associated symptoms. Other hypoglycemia was treated as moderate. The secondary outcomes were the changes in the efficacy variables from baseline to 52 weeks. The efficacy variables included HbA1c, body weight, fasting plasma glucose, homeostasis model assessment-insulin resistance (HOMAIR), adiponectin, waist circumference, blood pressure, and serum lipids in both trials. In the single-agent trial, 2-h postprandial glucose and insulin and Matsuda index were also measured. Matsuda index was calculated using postprandial glucose and insulin data. The secondary outcomes included the proportion of patients who achieved the target HbA1c level of < 7.0%. 2.4

Statistical considerations In the single-agent trial, we planned to include at least 100 patients in the 40-mg group according to the guideline for long-term clinical trials assessing safety [14]. This guideline recommends including 100 patients exposed for 1 year as part of the safety database. We also planned to include 50 patients in the 20-mg group because the safety of tofogliflozin was to be assessed mainly in the 40-mg (higher dose level) group. 2.5

Furthermore, we assumed that 20% of patients would discontinue the trial. As a result, a sample size of 192 patients (128 in the 40-mg group and 64 in the 20-mg group) was determined. In the add-on trial, we planned to include at least 100 patients treated with the tofogliflozin-sulfonylurea combination and 50 with each of other combinations in the 40-mg group according to the Japanese guideline for oral antidiabetic agents [15] in addition to the guideline mentioned above. This Japanese guideline recommends including 50 -- 100 patients exposed for each combination therapy as an adequate sample size for safety assessment. We also assumed that the drop-out rate would be 20%. As a result, a sample size of 384 patients (128 for the tofogliflozinsulfonylurea combination and 64 for each of other combinations) was determined. In the 20-mg group, a sample size of 32 patients was determined for each combination therapy. In the efficacy analysis, the full analysis set was defined as the primary analysis set. This analysis set included all randomized patients with type 2 diabetes who received at least one dose of trial medication and had at least one evaluable postrandomization measurement. The safety analysis included all patients who received at least one dose of trial medication. Baseline characteristics and outcome measures were summarized descriptively. Categorical variables were expressed as frequencies and percentages. Continuous variables were expressed as mean and standard deviation (SD). Continuous variables within each treatment group were compared between baseline and 52 weeks by using paired t-test. In the safety analysis, adverse events were coded and classified into preferred terms and system organ classes using Medical Dictionary for Regulatory Activities version 13.1. All data were analyzed by using SAS System Release 9.2 (SAS Institute, Cary, NC, USA). All reported p values are two sided (significance level 0.05). 3.

Results

3.1

Single-agent trial Patient population

3.1.1

The single-agent trial was conducted between November 2010 and June 2012 at 23 institutions. A total of 194 patients (65 in the 20-mg group and 129 in the 40-mg group) were enrolled into the trial (Figure 1). Of these, 191 patients (64, 20-mg group; 127, 40-mg group) received the trial medication and 169 (52 and 117, respectively) completed the trial. The baseline characteristics were balanced between the treatment groups (Table 1). Approximately two-thirds of the patients were men. Mean body mass index was 25.88 kg/m2 (SD 4.263) in the 20-mg group and 25.39 kg/m2 (4.652) in the 40-mg group. Safety During the trial, 49 patients (76.6%) in the 20-mg group and 110 (86.6%) in the 40-mg group experienced at least one 3.1.2

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194 patients ramdomized

20-mg treatment group n = 65

40-mg treatment group n = 129

No administration of trial medication n=1

No administration of trial medication n=2

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Safety population n = 64

Safety population n = 127

No measurement of HbA1c n=1 FAS population n = 127

FAS population n = 63 Medication terminated n = 11

Medication terminated n = 10

Completed in 52 weeks follow-up n = 117

Completed in 52 weeks follow-up n = 52

Figure 1. Flow chart of the patients enrolled into the single-agent trial. FAS: Full analysis set; HbA1c: Hemoglobin A1c.

Table 1. Baseline characteristics in the single-agent trial.

Age, year Sex (male) Weight, kg BMI, kg/m2 Previous treatment for type 2 diabetes HbA1c, % FPG, mg/dl (mmol/l) Duration of diabetes, year eGFR, ml/min/1.73 m2

20-mg (n = 63)

40-mg (n = 127)

58.7 ± 10.36 42 (66.7%) 68.95 ± 13.351 25.88 ± 4.263 18 (28.6%) 7.83 ± 0.96 157.2 ± 42.06 (8.72 ± 2.335) 5.630 ± 4.3275 80.51 ± 15.753

57.8 ± 11.07 84 (66.1%) 68.57 ± 15.810 25.39 ± 4.652 48 (37.8%) 7.83 ± 0.88 155.6 ± 35.59 (8.64 ± 1.976) 5.361 ± 5.2794 84.29 ± 19.272

Data are shown as mean ± SD. eGFR: Estimated glomerular filtration rate; FPG: Fasting plasma glucose; HbA1c: Hemoglobin A1c; SD: Standard deviation.

adverse event. Both doses of tofogliflozin were well tolerated. Only two (3.1%) and four (3.1%) patients in the 20- and 40-mg groups discontinued the trial because of adverse events, respectively. Common adverse events with the incidences of at least 5% are summarized in Table 2. Pollakiuria occurred in 8 (12.5%) and 18 (14.2%) patients in the 20- and 40-mg groups, and 752

thirst occurred in 7 (10.9%) and 16 (12.6%), respectively. Genital infection occurred in none and two (1.6%) patients in 20- and 40-mg groups. These two patients experienced vulvitis and vulvovaginal candidiasis. Cystitis occurred in three (4.7%) and three (2.4%) patients, urinary tract infection occurred in one (1.6%) and one (0.8%) patient in 20- and 40-mg groups, respectively. In addition, four (6.3%) and

Expert Opin. Pharmacother. (2014) 15(6)

Long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus

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Table 2. Summary of adverse events* in the single-agent trial.

Total patients with at least one adverse event Total number of adverse events Infections and infestations Nasopharyngitis Upper respiratory tract Investigations Blood ketone body increased Renal and urinary disorders Pollakiuria General disorders and administration site conditions Thirst Metabolism and nutrition disorders Hypoglycemia

20-mg (n = 64)

40-mg (n = 127)

49 (76.6%) 145

110 (86.6%) 310

16 (25.0%) 8 (12.5%)

42 (33.1%) 7 (5.5%)

4 (6.3%)

26 (20.5%)

8 (12.5%)

18 (14.2%)

7 (10.9%)

16 (12.6%)

4 (6.3%)

5 (3.9%)

*Incidence of at least 5%.

five (3.9%) patients experienced hypoglycemia in 20- and 40-mg groups, respectively; all instances were mild. Incidences of these events were similar between the treatment groups. Blood ketone body increased in a dose-related manner (6.3% in the 20-mg group vs 20.5% in the 40-mg group). Most adverse events were mild or moderate in severity. No severe or moderate hypoglycemia was reported. Furthermore, incidences of the adverse events were similar between the patients receiving the trial medication before and after breakfast (data not shown). Changes in laboratory variables are summarized in Table 3. In both treatment groups, mean values of serum uric acid, AST, ALT, and g-glutamyl transpeptidase (g-GTP) decreased from baseline to 52 weeks, whereas mean ketone body increased. In other laboratory variables, mean serum creatinine decreased and estimated glomerular filtration rate (eGFR) increased, but the changes from baseline to 52 weeks were small. Efficacy Both doses of tofogliflozin reduced HbA1c level throughout the treatment period (Figure 2). Mean reductions in HbA1c were apparent at 4 weeks and maintained thereafter. At 52 weeks, mean reductions in HbA1c from baseline were 0.67% (SD 0.67) and 0.66% (SD 0.71) in the 20- and 40-mg groups, respectively. The reductions in both groups were statistically significant compared with baseline (p < 0.0001). At 52 weeks, 22 patients (34.9%) in the 20-mg group and 52 (40.9%) in the 40-mg group achieved the target HbA1c of < 7.0%. In both groups, reductions in fasting plasma glucose were similar to those in HbA1c (data not shown). Tofogliflozin also reduced body weight consistently (Figure 3). At 52 weeks, mean reductions in body weight from baseline were 3.06 kg (SD 2.15) in the 20-mg group 3.1.3

and 3.44 kg (SD 2.60) in the 40-mg group (p < 0.0001 in both groups). Tofogliflozin treatment was associated with significant improvement of 2-h postprandial glucose and insulin, HOMA-IR, Matsuda index, waist circumference, and adiponectin (Table 4). In addition, tofogliflozin significantly lowered mean systolic blood pressure and elevated mean highdensity lipoprotein (HDL) cholesterol in both doses, whereas it did not affect low-density lipoprotein (LDL) cholesterol. Although data are not shown, changes in the efficacy variables were similar between the patients receiving the trial medication before and after breakfast. 3.2

Add-on trial Patient population

3.2.1

The add-on trial was conducted between November 2010 and June 2012 at 51 institutions. A total of 602 patients (178, 20-mg group; 424, 40-mg group) were enrolled (Figure 4). Of these, 9 patients (3, 20-mg group; 6, 40-mg group) did not receive the trial medication and 523 (154 and 369, respectively) completed the trial. The baseline characteristics were balanced among the subgroups by dose and background therapy (Table 5). Safety Adverse events occurred in 151 (86.3%) and 354 (84.7%) patients in the 20- and 40-mg groups, respectively. Of these, 10 (5.7%) and 19 (4.5%) patients discontinued the trial because of adverse events, respectively. The proportion of patients who had adverse events was similar among the subgroups based on dose and background therapy (Table 6). The most common adverse event was nasopharyngitis with the incidences of 22.1 -- 48.5% across the subgroups. Incidences of other common adverse events such as pollakiuria, thirst, genital infection, or urinary tract infection were similar to 3.2.2

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Table 3. Changes in laboratory data from the single-agent trial. 20-mg

40-mg Change

Renal

BUN

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Cr

eGFR

Baseline

mg/dl (mmol/l)

52 weeks

n mg/dl (mmol/l)

Baseline

n p value mg/dl (µmol/l)

52 weeks

n mg/dl (µmol/l)

Baseline

n p value ml/min/1.73 m2 n ml/min/1.73 m2 n p value mg/dl (µmol/l)

52 weeks

n mg/dl (µmol/l)

Baseline

n p value IU/l/37C (U/l)

52 weeks

n IU/l/37C (U/l)

Baseline

n p value IU/l/37C (U/l)

52 weeks

n IU/l/37C (U/l)

Baseline

n p value IU/l/37C (U/l)

52 weeks

n IU/l/37C (U/l)

Baseline 52 weeks

Uric acid

Hepatic

AST

ALT

g-GTP

Ketone body

Total ketone body

Baseline 52 weeks

Acetoacetic acid

Baseline 52 weeks

b-hydroxybutyric acid

Baseline 52 weeks

n p value µmol/l n µmol/l n p value µmol/l n µmol/l n p value µmol/l n µmol/l n p value

15.1 ± 3.5 (5.4 ± 1.26) 64 16.4 ± 3.2 (5.9 ± 1.12) 51 0.730 ± 0.157 (65 ± 13.9) 64 0.723 ± 0.179 (64 ± 15.8) 51 80.29 ± 15.73 64 82.81 ± 18.73 51 5.42 (322 64 4.85 (288 51

1.8 ± 3.1 (0.6 ± 1.10) 51 0.0001

-0.008 ± 0.068 (-1 ± 6.1) 51 0.3891

1.99 ± 7.88 51 0.0776

± 1.26 ± 74.7) ± 1.04 ± 61.9)

27.28 ± 9.78 (27 ± 9.8) 64 27.14 ± 10.25 (27 ± 10.2) 51 30.64 ± 16.57 (31 ± 16.6) 64 25.98 ± 12.70 (26 ± 12.7) 51 45.34 ± 36.39 (45 ± 36.4) 64 37.18 ± 28.90 (37 ± 28.9) 51 87.9 ± 68.31 64 172.6 ± 205.30 51 30.8 ± 20.55 64 55.3 ± 62.77 51 57.2 ± 49.65 64 117.3 ± 144.34 51

-0.52 ± 0.75 (-31 ± 44.4) 51 < 0.0001

-0.22 ± 11.59 (-0 ± 11.6) 51 0.8948

-5.78 ± 14.07 (-6 ± 14.1) 51 0.0050

-7.49 ± 14.49 (-7 ± 14.5) 51 0.0006

78.2 ± 207.06 51 0.0095

22.7 ± 62.48 51 0.0122

55.4 ± 146.00 51 0.0092

Change 15.3 ± 3.6 (5.5 ± 1.28) 127 17.0 ± 4.5 (6.1 ± 1.61) 117 0.711 ± 0.164 (63 ± 14.5) 127 0.680 ± 0.159 (60 ± 14.1) 117 84.29 ± 19.27 127 88.43 ± 19.47 117 4.96 (295 127 4.41 (262 117

1.9 ± 3.7 (0.7 ± 1.31) 117 < 0.0001

-0.026 ± 0.067 (-2 ± 5.9) 117 < 0.0001

3.73 ± 9.21 117 < 0.0001

± 1.26 ± 74.8) ± 1.16 ± 69.1)

26.25 ± 8.86 (26 ± 8.9) 127 23.90 ± 6.58 (24 ± 6.6) 117 29.28 ± 16.81 (29 ± 16.8) 127 22.64 ± 11.30 (23 ± 11.3) 117 44.09 ± 33.61 (44 ± 33.6) 127 33.31 ± 29.34 (33 ± 29.3) 117 108.3 ± 141.89 127 210.8 ± 185.49 117 34.5 ± 38.31 127 62.8 ± 50.54 117 73.9 ± 105.56 127 148.0 ± 137.96 117

Data are shown as mean ± SD. ALT: Alanine transaminase; AST: Aspartate transaminase; BUN: Blood urea nitrogen; Cr: Creatinine; eGFR: Estimated glomerular filtration rate; SD: Standard deviation; g-GTP: g-Glutamyl transpeptidase.

-0.52 ± 0.78 (-31 ± 46.2) 117 < 0.0001

-2.19 ± 9.68 (-2 ± 9.7) 117 0.0160

-6.58 ± 17.01 (-7 ± 17.0) 117 < 0.0001

-11.01 ± 21.78 (-11 ± 21.8) 117 < 0.0001

99.2 ± 201.07 117 < 0.0001

27.5 ± 51.35 117 < 0.0001

71.6 ± 152.88 117 < 0.0001

Long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus

(%) 0.5

-0.5

-1.0

-1.5

20-mg 40-mg

-2.0 4

0

8

12

16

20

24

28

32

36

40

44

48

52

(week) p value* (0 week vs 52 weeks)

Change in HbA1c (%) 20-mg (n)

-0.29 ± 0.37 (63)

-0.46 ± 0.45 -0.48 ± 0.57 -0.46 ± 0.74 -0.60 ± 0.73 -0.69 ± 0.79 -0.81 ± 0.77 -0.82 ± 0.74 -0.77 ± 0.74 -0.72 ± 0.73 -0.75 ± 0.69 -0.70 ± 0.63 -0.67 ± 0.67 (61) (61) (58) (53) (52) (52) (61) (56) (54) (52) (52) (51)

< 0.0001

40-mg (n)

-0.33 ± 0.43 (127)

-0.56 ± 0.41 -0.60 ± 0.51 -0.57 ± 0.58 -0.58 ± 0.62 -0.69 ± 0.62 -0.83 ± 0.64 -0.85 ± 0.66 -0.79 ± 0.68 -0.75 ± 0.66 -0.70 ± 0.66 -0.66 ± 0.66 -0.66 ± 0.71 (125) (125) (125) (123) (121) (118) (123) (122) (121) (121) (120) (117)

< 0.0001

Figure 2. Changes in HbA1c during the treatment period of the single-agent trial. The data are shown as mean and standard deviation. *Using paired t-test. HbA1c: Hemoglobin A1c.

(kg) 0 -1.0 Change in body weight

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Change in HbA1c

0

-2.0 -3.0 -4.0 -5.0 20-mg 40-mg

-6.0 -7.0 0

4

8

12

16

20

24

28

32

36

40

44

48

52

(week) p value* (0 week vs 52 weeks)

Change in body weight (kg) 20-mg (n)

-1.35 ± 0.98 (63)

-1.70 ± 1.14 -2.12 ± 1.07 -2.31 ± 1.35 -2.62 ± 1.41 -2.72 ± 1.44 -2.81 ± 1.58 -2.94 ± 1.72 -3.12 ± 1.84 -3.04 ± 1.85 -3.14 ± 2.00 -3.19 ± 2.13 -3.06 ± 2.15 (61) (61) (58) (56) (54) (53) (52) (52) (61) (52) (52) (51)

< 0.0001

40-mg (n)

-1.56 ± 1.05 (127)

-2.06 ± 1.48 -2.56 ± 1.86 -2.82 ± 2.13 -3.18 ± 2.29 -3.17 ± 2.40 -3.25 ± 2.37 -3.30 ± 2.49 -3.40 ± 2.55 -3.40 ± 2.56 -3.43 ± 2.58 -3.39 ± 2.60 -3.44 ± 2.60 (125) (122) (121) (124) (123) (121) (125) (123) (121) (120) (118) (117)

< 0.0001

Figure 3. Changes in body weight during the treatment period of the single-agent trial. The data are shown as mean and standard deviation. *Using paired t-test.

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Table 4. Changes in efficacy parameters in the single-agent trial. 20-mg

40-mg

Change 2-h Postprandial glucose

2-h Postprandial insulin

Baseline

mg/dl (mmol/l)

52 weeks

n mg/dl (mmol/l)

Baseline 52 weeks

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Insulin resistance

HOMA-IR

n p value µU/ml n µU/ml n p value

Baseline n 52 weeks n p value

Matsuda index

Baseline n 52 weeks

Waist circumference

Baseline

n p value cm n cm n p value µg/ml n µg/ml n p value mm Hg n mm Hg n p value mm Hg n mm Hg n p value mg/dl (mmol/l)

52 weeks

n mg/dl (mmol/l)

Baseline

n p value mg/dl (mmol/l)

52 weeks

n mg/dl (mmol/l)

Baseline

n p value mg/dl (mmol/l)

52 weeks

n mg/dl (mmol/l)

Baseline 52 weeks

Adiponectin

Baseline 52 weeks

Blood pressure

SBP

Baseline 52 weeks

DBP

Baseline 52 weeks

Serum lipid

TG

HDL-C

LDL-C

n p value

214.9 ± 68.4 (11.93 ± 3.795) 63 154.3 ± 39.8 (8.56 ± 2.210) 51 28.18 ± 16.65 63 19.79 ± 10.36 49 3.238 ± 2.027 63 2.076 ± 1.222 50 4.325 ± 2.920 62 6.222 ± 3.594 49 90.18 ± 10.68 63 87.52 ± 8.62 51 6.80 ± 3.53 63 7.85 ± 4.22 51 130.3 ± 14.0 63 124.0 ± 15.4 51 77.9 ± 10.2 63 74.2 ± 8.8 51 159.2 ± 122.0 (1.80 ± 1.377) 63 179.7 ± 345.8 (2.03 ± 3.904) 51 62.7 ± 18.3 (1.62 ± 0.472) 63 67.3 ± 21.9 (1.74 ± 0.567) 51 128.0 ± 32.6 (3.31 ± 0.842) 63 119.5 ± 31.3 (3.09 ± 0.810) 51

-59.6 ± 55.8 (1.34 ± 2.002) 51 < 0.0001

-9.48 ± 11.51 49 < 0.0001

-1.188 ± 1.480 50 < 0.0001

1.937 ± 1.914 48 < 0.0001

-3.05 ± 3.59 51 < 0.0001

1.26 ± 1.83 51 < 0.0001

-6.0 ± 15.2 51 0.0070

-3.9 ± 8.3 51 0.0015

26.9 ± 312.0 (0.30 ± 3.522) 51 0.5414

4.6 ± 12.1 (0.12 ± 0.314) 51 0.0086

-8.7 ± -27.7 (0.23 ± 0.717) 51 0.0290

Change 216.1 ± 64.2 (12.00 ± 3.564) 127 156.3 ± 44.9 (8.68 ± 2.494) 117 32.05 ± 31.48 126 19.60 ± 14.31 115 3.756 ± 3.351 127 2.063 ± 1.823 116 4.503 ± 3.170 125 7.333 ± 5.093 113 89.04 ± 11.13 127 85.82 ± 10.04 117 7.52 ± 3.44 127 8.60 ± 3.86 117 128.8 ± 15.4 127 126.0 ± 15.2 117 77.4 ± 11.1 127 76.4 ± 9.4 117 148.7 ± 104.1 (1.68 ± 1.175) 127 121.9 ± 91.1 (1.38 ± 1.028) 117 50.0 ± 16.9 (1.55 ± 0.438) 127 66.4 ± 20.4 (1.72 ± 0.5278) 117 121.7 ± 31.8 (3.15 ± 0.823) 127 121.4 ± 31.3 (3.14 ± 0.810) 117

-59.1 ± 49.1 (1.63 ± 2.089) 117 < 0.0001

-12.02 ± 21.97 114 < 0.0001

-1.573 ± 1.987 116 < 0.0001

2.847 ± 3.522 111 < 0.0001

-3.43 ± 4.03 117 < 0.0001

1.21 ± 1.68 117 < 0.0001

-3.3 ± 15.3 117 0.0224

-1.0 ± 10.4 117 0.2889

-24.0 ± 90.9 (-0.27 ± 1.027) 117 0.0051

6.4 ± 10.1 (0.17 ± 0.260) 117 < 0.0001

1.2 ± 22.9 (0.03 ± 0.593) 117 0.5597

Data are shown as mean ± SD. DBP: Diastolic blood pressure; HDL-C: High-density lipoprotein cholesterol; HOMA-IR: Homeostasis model of assessment-insulin resistance; LDL-C: Low-density lipoprotein cholesterol; SBP: Systolic blood pressure; SD: Standard deviation; TG: Triglyceride.

Long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus

602 patients ramdomized

40-mg treatment group n = 424

20-mg treatment group n = 178 SU/Glinide Biguanide n = 43 n = 33

DPP4 TZD α-Gl inhibitor n = 34 n = 33 n = 35

DPP4 SU/Glinide Biguanide TZD α-Gl inhibitor n = 150 n = 72 n = 68 n = 66 n = 68 No administration of trial medication n=6

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No administration of trial medication n=3 SU/Glinide n=1

TZD n=1

α-Gl n=1

SU/Glinide n=2

Safety population n = 418

Safety population n = 175

DPP4 SU/Glinide Biguanide TZD α-Gl inhibitor n = 148 n = 68 n = 68 n = 66 n = 68

DPP4 SU/Glinide Biguanide TZD α-Gl inhibitor n = 42 n = 33 n = 33 n = 32 n = 35 No measurement of HbA1c n=3 Biguanide n=1

TZD n=1

No measurement of HbA1c n=5

α-Gl n=1

SU/Glinide n=2

FAS population n = 172

TZD n=1

α-Gl n=1

DPP4 SU/Glinide Biguanide TZD α-Gl inhibitor n = 146 n = 67 n = 67 n = 65 n = 68

Medication terminated n = 18 TZD n=2

Biguanide n=1

FAS population n = 413

DPP4 SU/Glinide Biguanide TZD α-Gl inhibitor n = 42 n = 32 n = 32 n = 31 n = 35

SU/Glinide Biguanide n=8 n=3

Biguanide n=4

Medication terminated n = 44

DPP4 α-Gl inhibitor n=3 n=2

DPP4 SU/Glinide Biguanide TZD α-Gl inhibitor n = 17 n=4 n=9 n=8 n=6 Completed in 52 weeks follow-up n = 369

Completed in 52 weeks follow-up n = 154 DPP4 SU/Glinide Biguanide TZD α-Gl inhibitor n = 34 n = 29 n = 30 n = 28 n = 33

SU/Glinide Biguanide TZD α-Gl n = 129 n = 63 n = 58 n = 57

DPP4 inhibitor n = 62

Figure 4. Flow chart of the patients enrolled into the add-on trial. DPP4 inhibitor: Dipeptidyl peptidase-4 inhibitor; FAS: Full analysis set; HbA1c: Hemoglobin A1c; SU: Sulfonylureas; TZD: Thiazolidinedione; a-GI: a-Glucosidase inhibitor.

those seen in the single-agent trial. Most adverse events were mild or moderate in severity. Hypoglycemia occurred in 7 patients (4.0%) in the 20-mg group and 20 (4.8%) in the 40-mg group. Although the

incidence of hypoglycemia was similar between the treatment groups, patients receiving the tofogliflozin-sulfonylurea combination experienced hypoglycemia more frequently than those receiving other combinations. No severe hypoglycemia

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758

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60.6 ± 8.48 31 (73.8%) 64.21 ± 8.77 24.18 ± 2.49 8.23 ± 0.79 170.8 ± 37.25 (9.48 ± 2.068) 9.24 ± 6.52

56.3 ± 8.70 21 (65.6%) 67.28 ± 12.24 24.68 ± 3.08 7.70 ± 0.69 150.2 ± 24.84 (8.34 ± 1.379) 7.82 ± 5.24

Biguanide (n = 32)

58.9 ± 9.95 19 (59.4%) 72.78 ± 14.11 27.51 ± 4.74 8.13 ± 1.06 160.0 ± 40.01 (8.88 ± 2.221) 7.22 ± 6.45

TZD (n = 32)

58.2 ± 11.17 20 (64.5%) 66.73 ± 13.86 25.42 ± 3.51 8.14 ± 1.06 164.2 ± 42.42 (9.11 ± 2.355) 5.89 ± 4.67

a-GI (n = 31)

56.6 ± 11.68 22 (62.9%) 70.44 ± 16.78 26.22 ± 4.87 8.38 ± 0.95 171.1 ± 43.01 (9.50 ± 2.387) 7.41 ± 5.89

DPP4 inhibitor (n = 35) 58.7 ± 10.53 273 (66.1%) 68.46 ± 14.18 25.68 ± 4.42 8.12 ± 0.89 161.9 ± 35.83 (8.99 ± 1.989) 7.71 ± 6.18

All (n = 413)

61.3 ± 9.49 103 (70.5%) 66.25 ± 13.02 24.88 ± 3.92 8.26 ± 0.86 168.2 ± 38.01 (9.34 ± 2.110) 9.44 ± 6.98

SU/glinide (n = 146)

57.4 ± 10.98 43 (64.2%) 72.21 ± 15.66 26.82 ± 4.84 7.98 ± 0.91 157.7 ± 34.40 (8.75 ± 1.910) 7.67 ± 5.67

Biguanide (n = 67)

56.0 ± 12.13 43 (64.2%) 72.33 ± 15.35 27.17 ± 4.80 7.97 ± 0.93 152.2 ± 30.07 (8.45 ± 1.669) 5.91 ± 4.73

TZD (n = 67)

DPP4 inhibitor (n = 68) 60.2 ± 9.92 56.0 ± 9.83 41 (63.1%) 43 (63.2%) 66.82 ± 11.52 67.23 ± 15.00 25.13 ± 3.97 25.32 ± 4.54 8.02 ± 0.86 8.19 ± 0.89 158.5 ± 36.34 165.2 ± 35.07 (8.80 ± 2.017) (9.17 ± 1.947) 6.70 ± 6.04 6.80 ± 5.42

a-GI (n = 65)

84.41 ± 17.97 81.14 ± 17.10 87.35 ± 20.23 83.01 ± 14.73 81.69 ± 20.06 89.32 ± 17.04 84.08 ± 18.65 82.21 ± 15.99 83.06 ± 19.31 86.91 ± 17.37 83.69 ± 21.71 86.68 ± 21.14

58.2 ± 10.03 113 (65.7%) 68.10 ± 13.45 25.53 ± 3.95 8.13 ± 0.93 163.8 ± 38.46 (9.09 ± 2.135) 7.62 ± 5.89

SU/glinide (n = 42)

40-mg

Data are shown as mean ± SD. DPP4 inhibitor: Dipeptidyl peptidase-4 inhibitor; eGFR: Estimated glomerular filtration rate; FPG: Fasting plasma glucose; HbA1c: Hemoglobin A1c; SU: Sulfonylureas; TZD: Thiazolidinedione; a-GI: a-Glucosidase inhibitor.

Age, year Sex (male) Weight, kg BMI, kg/m2 HbA1c, % FPG, mg/dl (mmol/l) Duration of diabetes, year eGFR, ml/min/ 1.73 m2

All (n = 172)

20-mg

Table 5. Baseline characteristics in the add-on trial.

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1 (3.0%) 1 (3.0%) 1 1 1 1 0 1 (3.0%) 0 0 0 0

0 0 5 (11.9%) 0 0 1 (2.4%) 0 4 (9.5%) 0 0 1 (2.4%) 0

(3.0%) (3.0%) (3.0%) (3.0%)

8 (24.2%) 7 (21.2%)

69

102

14 (33.3%) 0

28 (84.8%)

Biguanide (n = 33)

37 (88.1%)

SU/Glinide (n = 42)

2 (6.1%)

2 (6.1%)

4 (12.1%)

1 (3.0%)

12 (36.4%)

2 (6.1%)

0 2 (6.1%) 0 1 (3.0%)

1 (3.0%) 2 (6.1%)

16 (48.5%) 4 (12.1%)

102

30 (90.9%)

TZD (n = 33)

0

0

1 (3.1%)

0

2 (6.3%)

0

0 0 0 0

3 (9.4%) 1 (3.1%)

10 (31.3%) 2 (6.3%)

62

25 (78.1%)

a-GI (n = 32)

0

0

0

2 (5.7%)

4 (11.4%)

0

0 3 (8.6%) 1 (2.9%) 0

1 (2.9%) 1 (2.9%)

16 (45.7%) 0

80

31 (88.6%)

DPP4 inhibitor (n = 35)

*Incidence of at least 5%. DPP4 inhibitor: Dipeptidyl peptidase-4 inhibitor; SU: Sulfonylureas; TZD: Thiazolidinedione; a-GI: a-Glucosidase inhibitor.

Total patients with at 151 (86.3%) least one adverse event Total number of 415 adverse events Infections and infestations Nasopharyngitis 64 (36.6%) Upper respiratory 13 (7.4%) tract infection Gastroenteritis 6 (3.4%) Cystitis 5 (2.9%) Gastrointestinal disorders Constipation 6 (3.4%) Dental caries 6 (3.4%) Diarrhoea 2 (1.1%) Abdominal pain 3 (1.7%) upper Gastric ulcer 2 (1.1%) Investigations Blood ketone 23 (13.1%) body increased Urine ketone 3 (1.7%) body increased Urine output 5 (2.9%) increased b 2 Microglobulin 3 (1.7%) urine increased Blood lactic acid 2 (1.1%) increased

All (n = 175)

20-mg

Table 6. Summary of adverse events* in the add-on trial.

(5.7%) (2.9%) (3.6%) (2.4%)

1 (0.2%)

8 (1.9%)

6 (1.4%)

9 (2.2%)

47 (11.2%)

3 (0.7%)

24 12 15 10

10 (2.4%) 9 (2.2%)

145 (34.7%) 31 (7.4%)

1062

354 (84.7%)

All (n = 418)

1 (0.7%)

5 (3.4%)

1 (0.7%)

1 (0.7%)

13 (8.8%)

1 (0.7%)

12 (8.1%) 6 (4.1%) 9 (6.1%) 5 (3.4%)

4 (2.7%) 1 (0.7%)

62 (41.9%) 6 (4.1%)

432

129 (87.2%)

SU/Glinide (n = 148)

(4.4%) (1.5%) (1.5%) (1.5%)

0

0

1 (1.5%)

1 (1.5%)

5 (7.4%)

0

3 1 1 1

1 (1.5%) 1 (1.5%)

15 (22.1%) 12 (17.6%)

149

61 (89.7%)

TZD (n = 68)

0

2 (2.9%)

1 (1.5%)

2 (2.9%)

20 (29.4%)

1 (1.5%)

3 (4.4%) 1 (1.5%) 1 (1.5%) 0

1 (1.5%) 2 (2.9%)

20 (29.4%) 1 (1.5%)

167

58 (85.3%)

40-mg Biguanide (n = 68)

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(6.1%) (6.1%) (3.0%) (6.1%)

0

1 (1.5%)

0

1 (1.5%)

1 (1.5%)

1 (1.5%)

4 4 2 4

1 (1.5%) 4 (6.1%)

18 (27.3%) 6 (9.1%)

155

51 (77.3%)

a-GI (n = 66)

0

0

3 (4.4%)

4 (5.9%)

8 (11.8%)

0

2 (2.9%) 0 2 (2.9%) 0

3 (4.4%) 1 (1.5%)

30 (44.1%) 6 (8.8%)

159

55 (80.9%)

DPP4 inhibitor (n = 68)

Long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus

759

760 SU/Glinide (n = 42)

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4 (12.1%) 1 (3.0%) 0 0 2 (6.1%) 1 (3.0%) 0 1 (3.0%) 0 0 2 (6.1%)

0 1 (3.0%) 0 1 (3.0%) 1 (3.0%) 0 0 1 (3.0%) 1 (3.0%) 1 (3.0%)

0 2 (6.1%)

TZD (n = 33)

1 (3.0%)

3 (9.1%) 1 (3.0%)

Biguanide (n = 33)

1 (3.1%)

0

0

2 (6.3%)

0 0

2 (6.3%)

0

1 (3.1%) 0

2 (6.3%)

1 (3.1%) 1 (3.1%)

a-GI (n = 32)

0

2 (5.7%)

1 (2.9%)

0

0 1 (2.9%)

0

1 (2.9%)

1 (2.9%) 2 (5.7%)

4 (11.4%)

2 (5.7%) 1 (2.9%)

DPP4 inhibitor (n = 35)

*Incidence of at least 5%. DPP4 inhibitor: Dipeptidyl peptidase-4 inhibitor; SU: Sulfonylureas; TZD: Thiazolidinedione; a-GI: a-Glucosidase inhibitor.

Musculoskeletal and connective tissue disorders Back pain 8 (4.6%) 2 (4.8%) Periarthritis 5 (2.9%) 0 General disorders and administration site conditions Thirst 14 (8.0%) 3 (7.1%) Injury, poisoning, and procedural complications Contusion 3 (1.7%) 0 Arthropod sting 4 (2.3%) 1 (2.4%) Skin and subcutaneous tissue disorders Eczema 1 (0.6%) 0 Renal and urinary disorders Pollakiuria 11 (6.3%) 6 (14.3%) Nervous system disorders Dizziness 2 (1.1%) 0 Carotid 1 (0.6%) 0 arteriosclerosis Dizziness postural 4 (2.3%) 1 (2.4%) Metabolism and nutrition disorders Hypoglycemia 7 (4.0%) 5 (11.9%) Eye disorders Cataract 4 (2.3%) 1 (2.4%) Vascular disorders Hypertension 4 (2.3%) 0

All (n = 175)

20-mg

Table 6. Summary of adverse events* in the add-on trial (continued).

8 (1.9%)

6 (1.4%)

20 (4.8%)

1 (0.2%)

6 (1.4%) 5 (1.2%)

28 (6.7%)

17 (4.1%)

14 (3.3%) 4 (1.0%)

42 (10.0%)

15 (3.6%) 7 (1.7%)

All (n = 418)

5 (3.4%)

2 (1.4%)

12 (8.1%)

0

1 (0.7%) 0

12 (8.1%)

7 (4.7%)

5 (3.4%) 0

15 (10.1%)

7 (4.7%) 3 (2.0%)

SU/Glinide (n = 148)

0

2 (2.9%)

2 (2.9%)

0

0 4 (5.9%)

4 (5.9%)

2 (2.9%)

3 (4.4%) 0

5 (7.4%)

1 (1.5%) 0

TZD (n = 68)

1 (1.5%)

1 (1.5%)

2 (2.9%)

0

0 0

5 (7.4%)

1 (1.5%)

4 (5.9%) 3 (4.4%)

7 (10.3%)

3 (4.4%) 0

40-mg Biguanide (n = 68)

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1 (1.5%)

1 (1.5%)

3 (4.5%)

0

4 (6.1%) 0

4 (6.1%)

2 (3.0%)

1 (1.5%) 0

7 (10.6%)

1 (1.5%) 2 (3.0%)

a-GI (n = 66)

1 (1.5%)

0

1 (1.5%)

1 (1.5%)

1 (1.5%) 1 (1.5%)

3 (4.4%)

5 (7.4%)

1 (1.5%) 1 (1.5%)

8 (11.8%)

3 (4.4%) 2 (2.9%)

DPP4 inhibitor (n = 68)

Y. Tanizawa et al.

Long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus

A. HbA1c 20-mg TZD (n = 32)

α-Gl (n = 27)

40-mg

DPP4 inhibitor (n = 32)

(%) 0 -0.2

-0.4

-0.4 Change in HbA1c

-0.2

-0.6 -0.8 -1.0 -1.2

TZD (n = 58)

α-Gl (n = 57)

-0.80 ± 0.73 -0.82 ± 0.60 (< 0.0001) (< 0.0001)

-0.93 ± 0.65 (< 0.0001)

All SU/Glinide Biguanide (n = 366) (n = 128) (n = 63)

DPP4 inhibitor (n = 60)

-0.6 -0.8 -1.0 -1.2

-1.4

-1.4

-1.6

-1.6

-1.8

-1.8 -0.77 ± 0.72 -0.71 ± 0.58 (< 0.0001) (< 0.0001)

-0.71 ± 0.55 -0.84 ± 0.85 (< 0.0001) (< 0.0001)

-0.84 ± 0.72 (< 0.0001)

-0.78 ± 0.88 (< 0.0001)

α-Gl (n = 27)

DPP4 inhibitor (n = 32)

-0.87 ± 0.75 -0.87 ± 0.81 (< 0.0001) (< 0.0001)

-0.93 ± 0.86 (< 0.0001)

B. Body weight 20-mg

40-mg

All SU/Glinide Biguanide (n = 152) (n = 34) (n = 29)

TZD (n = 30)

0

(kg) 0

-1.0

-1.0 Change in body weight

(kg)

Change in body weight

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Change in HbA1c

(%) 0

All SU/Glinide Biguanide (n = 152) (n = 34) (n = 29)

-2.0 -3.0 -4.0 -5.0 -6.0

All (n = 367)

SU/Glinide Biguanide (n = 128) (n = 63)

-2.98 ± 2.63 (< 0.0001)

-2.80 ± 2.18 -3.88 ± 3.31 (< 0.0001) (< 0.0001)

TZD (n = 58)

α-Gl (n = 57)

DPP4 inhibitor (n = 61)

-2.0 -3.0 -4.0 -5.0 -6.0 -7.0

-7.0

-8.0

-8.0 -2.51 ± 2.47 -1.64 ± 2.20 (< 0.0001) (< 0.0001)

-2.94 ± 2.05 -2.42 ± 2.76 (< 0.0001) (< 0.0001)

-3.03 ± 2.34 (< 0.0001)

-2.69 ± 2.81 (< 0.0001)

-2.05 ± 3.01 -3.86 ± 2.52 (< 0.0001) (< 0.0001)

-2.50 ± 1.86 (< 0.0001)

Figure 5. Changes in HbA1c and body weight at 52 weeks of the add-on trial. The data are shown as mean and standard deviation. DPP4 inhibitor: Dipeptidyl peptidase-4 inhibitor; HbA1c: Hemoglobin A1c; SU: Sulfonylureas; TZD: Thiazolidinedione; a-GI: a-Glucosidase inhibitor.

was reported, whereas three patients (two in the 20-mg group and one in the 40-mg group) experienced moderate hypoglycemia. These three patients received the tofogliflozinsulfonylurea combination. Efficacy Tofogliflozin significantly reduced HbA1c from baseline to 52 weeks (Figure 5A). Mean reductions in HbA1c ranged from 0.71 to 0.84% in the 20-mg group and from 0.80 to 0.93% in the 40-mg group with consistent reductions regardless of the background therapies (P < 0.0001 in all subgroups). At 52 weeks, 55 (32.0%) and 142 (34.4%) patients 3.2.3

in the 20- and 40-mg groups, respectively, achieved the target HbA1c of < 7.0%. Tofogliflozin also reduced fasting plasma glucose (data not shown). These effects on glycemic markers were accompanied by significant weight loss (Figure 5B). At 52 weeks, mean reductions in body weight ranged from 1.64 to 3.03 kg in the 20-mg group and from 2.05 to 3.88 kg in the 40-mg group (p < 0.0001 in all subgroups). Changes in other efficacy variables are summarized in Table 7. Tofogliflozin significantly improved HOMA-IR, waist circumference, and adiponectin. It also significantly lowered systolic/diastolic blood pressure and elevated HDL cholesterol.

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Table 7. Changes in efficacy parameters in the add-on trial. 20-mg

40-mg Change

HOMA-IR

Baseline n 52 weeks

Waist circumference

Baseline

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52 weeks

Adiponectin

Baseline 52 weeks

Blood pressure

SBP

Baseline 52 weeks

DBP

Baseline 52 weeks

Serum lipid

TG

Baseline

52 weeks

HDL-C

Baseline

52 weeks

LDL-C

Baseline

52 weeks

n p value cm n cm n p value µg/ml n µg/ml n p value mm Hg n mm Hg n p value mm Hg n mm Hg n p value mg/dl (mmol/l) n mg/dl (mmol/l) n p value mg/dl (mmol/l) n mg/dl (mmol/l) n p value mg/dl (mmol/l) n mg/dl (mmol/l) n p value

3.139 ± 1.948 170 1.916 ± 1.376 149 89.44 ± 10.35 172 87.30 ± 10.54 152 9.35 ± 6.83 172 10.69 ± 7.97 152

-1.244 ± 1.487 147 < 0.0001

-2.36 ± 3.51 152 < 0.0001

1.33 ± 3.30 152 < 0.0001

129.6 ± 14.9 172 126.3 ± 14.3 152

-3.1 ± 14.2 152 0.0077

77.6 ± 10.3 172 75.8 ± 9.4 152

-2.1 ± 10.2 152 0.0121

140.0 ± 95.1 (1.58 ± 1.073) 172 135.2 ± 118.8 (1.53 ± 1.337) 151 61.4 ± 17.2 (1.59 ± 0.444) 172 65.2 ± 18.8 (1.69 ± 0.486) 152 125.8 ± 29.2 (3.25 ± 0.754) 172 123.7 ± 30.9 (3.20 ± 0.800) 152

-5.9 ± 71.1 (-0.08 ± 0.811) 151 0.3098

4.0 ± 9.0 (0.10 ± 0.233) 152 < 0.0001

-1.6 ± 25.9 (-0.04 ± 0.671) 152 0.4559

Change 4.033 ± 18.556 410 1.848 ± 1.643 364 89.73 ± 10.20 413 87.17 ± 10.15 366 8.47 ± 5.27 413 9.66 ± 5.61 366 131.2 ± 13.3 413 126.0 ± 13.5 367 77.1 ± 9.9 413 75.0 ± 10.0 367 139.2 ± 87.7 (1.57 ± 0.990) 413 122.5 ± 86.9 (1.38 ± 0.981) 366 59.8 ± 16.8 (1.55 ± 0.435) 413 66.0 ± 18.8 (1.71 ± 0.486) 366 122.5 ± 28.1 (3.17 ± 0.728) 413 122.8 ± 29.9 (3.17 ± 0.774) 366

-2.260 ± 19.464 361 0.0280

-2.50 ± 4.29 366 < 0.0001

1.19 ± 2.09 366 < 0.0001

-5.2 ± 12.5 367 < 0.0001

-2.2 ± 9.2 367 < 0.0001

-16.0 ± 79.6 (-0.18 ± 0.899) 366 0.0001

6.5 ± 9.8 (0.17 ± 0.255) 366 < 0.0001

1.2 ± 21.2 (0.03 ± 0.549) 366 0.2640

Data are shown as mean ± SD. DBP: Diastolic blood pressure; HDL-C: High-density lipoprotein cholesterol; HOMA-IR: Homeostasis model of assessment-insulin resistance; LDL-C: Low-density lipoprotein cholesterol; SBP: Systolic blood pressure; SD: Standard deviation; TG: Triglyceride.

4.

Discussion

Safety In our trials, both doses of tofogliflozin were well tolerated during the treatment period of 52 weeks. Most adverse events 4.1

762

were mild or moderate in severity, and few patients discontinued the trials because of adverse events. The safety profiles of tofogliflozin in our trials were similar to those observed in our 24-week, randomized controlled trial. No new safety issues were identified.

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Long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus

The incidence of hypoglycemia was low in both doses. This might be due to the high selectivity of tofogliflozin to SGLT2. In the previous nonclinical studies, the contribution of SGLT1 to renal glucose reabsorption was greater under hypoglycemic conditions than under hyperglycemic conditions [13] and the selectivity of tofogliflozin to SGLT2 versus SGLT1 was the highest among the SGLT2 inhibitors [12]. Furthermore, tofogliflozin did not reduce renal glucose reabsorption under hypoglycemic conditions [13]. These characteristics of tofogliflozin may have an advantage for less risk of hypoglycemia. The incidence of hypoglycemia was similar between the treatment groups, but it was higher in the subgroups of patients receiving the tofogliflozin-sulfonylurea combination. In addition, moderate episodes were reported only in these patients. To date, the use of the SGLT2 inhibitors has not been found to increase the risk of hypoglycemia because reduction in blood glucose lowers the glucose load filtered by the kidneys and limits further glucose excretion [16]. In contrast, sulfonylurea treatment is frequently associated with hypoglycemia. Thus, careful glucose monitoring is needed when tofogliflozin is added to sulfonylureas. Although genital and urinary tract infections are the most common adverse events associated with the SGLT2 inhibitors [17], their incidences were < 5% in our trials. The previous dapagliflozin study also demonstrated no apparent dose relationship of the frequency of events of urinary tract and genital infections in Japanese patients with type 2 diabetes [18], which may, in part, reflect the high percentage of men in the studies conducted in Japan. Vulvitis, vulvovaginal candidiasis, cystitis, and urinary tract infection were observed in both the singleagent and the add-on trials, but all these events were mild or moderate in severity and transient. Furthermore, renal impairment such as increased in serum creatinine or decreased in eGFR -- other safety concern about the SGLT2 inhibitors -- was not observed in our trials. These results suggest the preferable safety profile of tofogliflozin. However, our sample sizes were not large enough to accurately estimate the incidences of uncommon adverse events and laboratory changes precisely. To determine whether tofogliflozin induces genital infection, urinary tract infection, or renal impairment, further large-scale and long-term clinical studies are needed. In contrast, pollakiuria and thirst occurred frequently in our trials. Inhibition of SGLT2 sometimes results in volume depletion because of osmotic diuresis. Thus, volume status of the patients should be assessed when administering tofogliflozin. It is also important to increase intake of water especially for elderly patients. In addition, blood ketone body increased in a dose-related manner. This increase was derived from the increased liver metabolism of fatty acids into ketones secondary due to urinary glucose excretion. Although increase in blood ketone body was transient and accompanied with no clinical symptom in our trials, ketone body level should be carefully monitored in long-term reallife practice.

In laboratory tests, tofogliflozin reduced mean values of ALT, AST, g-GTP, and serum uric acid. Of these changes, the improvement in hepatic function might result from reduction in hepatic lipid content. In the previous trials, dapagliflozin reduced hepatic lipid content and this reduction was associated with urinary glucose excretion [19]. The inhibition of sodium-coupled uric acid reabsorption in the proximal renal tubules may be responsible for the decrease in serum uric acid concentrations observed in other clinical trials [20,21]. These changes may be a potential benefit of the SGLT2 inhibitors because serum uric acid and liver transaminases are often elevated in patients with type 2 diabetes.

Efficacy In the single-agent trial, both doses of tofogliflozin provided similar reductions in HbA1c throughout the treatment period. Mean reductions in HbA1c at 52 weeks were 0.67 and 0.66% in the 20- and 40-mg groups, respectively. These results are consistent with those of the 24-week, randomized controlled trial, which compared tofogliflozin (10, 20 or 40 mg) with placebo. In that 24-week trial, mean HbA1c reductions at 24 weeks were 1.02 and 0.87% in the 20- and 40-mg groups, respectively. In addition, our results are consistent with the mean HbA1c reductions of 0.55 -- 0.90% in patients treated with various doses of dapagliflozin [17]. Although we did not use placebo as a comparator, these consistencies with the previous results support the efficacy of tofogliflozin in the long term. In the add-on trial, tofogliflozin produced a long-term reduction in HbA1c over 52 weeks in patients whose hyperglycemia was inadequately controlled with an oral antidiabetic agent. The magnitude of changes in HbA1c was similar to that in the single-agent trial and was consistent regardless of the background therapies. These results indicate that tofogliflozin can be used in any combination with existing oral antidiabetic agents. Considering its insulin-independent mechanism of action, the combination of tofogliflozin and other oral antidiabetic agents may have application throughout the natural history of diabetes. The glucose-lowering effect of tofogliflozin was accompanied by significant weight loss. Weight gain is one of the major adverse reactions to antidiabetic agents such as sulfonylureas, thiazolidinediones, and insulin. In our add-on trial, tofogliflozin reduced mean body weight by > 1.6 kg even in the subgroups of patients receiving sulfonylureas or pioglitazone. This weight loss was considered to be derived from reduced body fat secondary to caloric loss. In a clinical trial measuring body composition, dapagliflozin reduced total body weight, and about three-quarters of the total weight loss was attributed to reduction in fat mass [19]. Moreover, decrease in total body weight was associated with urinary glucose excretion [19]. Caloric loss might also result in the improvement of waist circumference, adiponectin, and insulin resistance in our trials. 4.2

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In other efficacy variables, tofogliflozin lowered blood pressure. Reductions in blood pressure might arise mainly from diuresis due to SGLT2 inhibition, because dapagliflozin also lowered blood pressure in the previous clinical trials [8,19,20]. Tofogliflozin elevated HDL cholesterol, tended to lower triglycerides, and affected neutral for LDL cholesterol in our trials. Although our results suggest the favorable effects of tofogliflozin on serum lipids, we should monitor lipid profiles carefully in clinical practice setting because it was reported that canagliflozin elevated LDL cholesterol in a dose-related manner [22]. Limitations First, our trials were designed to detect adverse events occurring frequently during the long-term treatment. Thus, the sample sizes were not large enough to assess the uncommon risks including cardiovascular events and cancer. Second, the majority of subjects were men, these studies might not provide sufficient examination of women-specific events. Third, we adopted the open-label design without placebo group, and adverse events were assessed by the investigators who were aware of the allocated doses. Thus, the open-label design might induce bias in assessing the safety outcomes, and we could not assess the extent of the placebo response bound to be here. However, the results were in good agreement with those from our previous 24-week placebo-controlled trial, and therefore, we further confirmed safety and efficacy of tofogliflozin. Fourth, we did not verify the efficacy and safety in combination with insulin and GLP-1 in these trials.

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5.

Conclusion

Tofogliflozin (20 or 40 mg, once daily) is an effective and tolerable antidiabetic agent both as monotherapy and in combination with other oral antidiabetic agents. Few patients discontinued the trials because of adverse events, and most adverse events were mild or moderate in severity. The incidences of hypoglycemia and urinary tract infections were low in both trials, whereas pollakiuria and thirst occurred frequently. Its effects on glycemic control and body weight were sustained during the treatment period of 52 weeks. In the add-on trial, these effects were consistent regardless of the background therapies. Thus, it can be used in any combination with existing antidiabetic therapies. Further large-scale study is warranted to determine the effects of tofogliflozin on cardiovascular events and to investigate safety concerns.

Acknowledgements Writing and editorial assistance was provided by Mieko Onuki from EDIT, Inc. This study was previously presented at 49th Annual Meeting of European Association for the Study of Diabetes, in Barcelona, 23 -- 27 September 2013.

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Declaration of interest These trials registered to the Japan Pharmaceutical Information Center (Japic) Clinical Trials Information as JapicCTI-101351 and 101352. These trials were supported by Chugai Pharmaceutical Co., Ltd. Writing and editorial assistance was provided by Mieko Onuki from EDIT, Inc. which was contracted by Sanofi K.K. and Kowa Pharmaceutical Co., Ltd for this service. Y Tanizawa received honoraria for lectures from Novartis Pharma K.K., Takeda Pharmaceutical Co., Ltd, MSD K.K., Ono Pharmaceutical Co., Ltd, Sanofi K.K., Mitsubishi Tanabe Pharma Corp., Novo Nordisk Pharma Ltd, Nippon Boehringer Ingelheim Co., Ltd, and Dainippon Sumitomo Pharma Co., Ltd and scholarship funds from Kowa Pharmaceutical Co., Ltd, Dainippon Sumitomo Pharma Co., Takeda Pharmaceutical Co., Ltd, MSD K.K., Astellas Pharma, Inc., Daiichi Sankyo Co., Ltd, Kyowa Hakko Kirin Co., Ltd, Sanofi K.K., Novartis Pharma K.K., and Nippon Boehringer Ingelheim Co., Ltd. K Kaku received honoraria for lectures from MSD K.K., Novartis Pharma K.K., Takeda Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd, Kowa Pharmaceutical Co., Ltd, Novo Nordisk Pharma Ltd, Sanofi K.K., and Dainippon Sumitomo Pharma Co. and unrestricted grants from MSD K.K., Nippon Boehringer Ingelheim Co., Ltd, Novartis Pharma K. K., Takeda Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd, Novo Nordisk Pharma Ltd, Sanofi K.K., Dainippon Sumitomo Pharma Co., Astellas Pharma, Inc., and AstraZeneca K.K. E Araki received honoraria for lectures from MSD K.K., Sanofi K. K., Daiichi Sankyo Co., Ltd, Mitsubishi Tanabe Pharma Corp., Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd, Nippon Boehringer Ingelheim Co., Ltd, Novartis Pharma K.K., Kowa Pharmaceutical Co., Ltd, and Kowa Co., Ltd and scholarship funds from Mitsubishi Tanabe Pharma Corp., Sanofi K.K., Nippon Boehringer Ingelheim Co., Ltd, Astellas Pharma, Inc., Dainippon Sumitomo Pharma Co., Ltd, Pfizer Japan, Inc., and MSD K.K. K Tobe received honoraria for lectures from Takeda Pharmaceutical Co., Ltd and Mitsubishi Tanabe Pharma Corp. and scholarship funds from Novo Nordisk Pharma Ltd, Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd, MSD K.K., Astellas Pharma, Inc., Sanofi K.K., Iryouhoujin Shichitokukai, Seida Sadayoshi, Mitsubishi Tanabe Pharma Corp., Takeda Pharmaceutical Co., Ltd, and Chugai Pharmaceutical Co., Ltd. Y Terauchi received honoraria for lectures from MSD K.K., Ono Pharmaceutical Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd, Novartis Pharma K.K., Takeda Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd, Sanwa Kagaku Kenkyusho Co., Ltd, Kowa Pharmaceutical Co., Ltd, Novo Nordisk Pharma Ltd, Eli Lilly Japan K.K., Sanofi K. K., Dainippon Sumitomo Pharma Co., Ltd, Shionogi &

Expert Opin. Pharmacother. (2014) 15(6)

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Long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus

Co., Ltd, Kissei Pharmaceutical Co., Ltd, Bayer Yakuhin, Ltd, Astellas Pharma, Inc., Pfizer Japan, Inc., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd, Teijin Pharma Ltd, Mochida Pharmaceutical Co., Ltd, Roche Diagnostics K. K., and Johnson & Johnson K.K. and unrestricted grants from MSD K.K., Ono Pharmaceutical Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd, Novartis Pharma K.K., Takeda Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd, Sanwa Kagaku Kenkyusho Co., Ltd, Kowa Pharmaceutical Co., Ltd, Novo Nordisk Pharma Ltd, Eli Lilly Japan K.K., Sanofi K. K., Dainippon Sumitomo Pharma Co., Ltd, Shionogi & Co., Ltd, Kissei Pharmaceutical Co., Ltd, Bayer Yakuhin, Ltd, Astellas Pharma, Inc., and AstraZeneca K.K. K Utsunomiya received honoraria for lectures from MSD K.K., Ono Pharmaceutical Co., Ltd, Nippon Boehringer Ingelheim Co., Novartis Pharma K.K., Takeda Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd, Sanwa Kagaku Kenkyusho Co., Ltd, Kowa Pharmaceutical Co., Ltd, Novo Nordisk Pharma Ltd, Eli Lilly Japan K.K., Sanofi K.K., Dainippon Sumitomo Pharma Co., Ltd, Shionogi & Co., Ltd, Kissei Pharmaceutical Co., Ltd, Bayer Yakuhin, Ltd, Astellas Pharma, Inc., Pfizer Japan, Inc., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd, Teijin Pharma Ltd, Mochida Pharmaceutical Co., Ltd, Roche Diagnostics K.K., and Johnson & Johnson K.K. and unrestricted grants from MSD K.K., Ono Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Pharmaceutical Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd, Novartis Pharma K.K., Takeda Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd, Sanwa Kagaku Kenkyusho Co., Ltd, Kowa Pharmaceutical Co., Ltd, Novo Nordisk Pharma Ltd, Eli Lilly Japan K.K., Sanofi K.K., Dainippon Sumitomo Pharma Co., Ltd, Shionogi & Co., Ltd, Kissei Pharmaceutical Co., Ltd, Bayer Yakuhin, Ltd, Astellas Pharma, Inc., and AstraZeneca K.K. Y Iwamoto received honoraria for lectures from MSD K.K., Sanofi K.K., and Eli Lilly Japan K.K. H Watada received lecture fees from Nippon Boehringer Ingelheim Co., Ltd, Sanofi K.K., Ono Pharmaceutical Co., Ltd, Novo Nordisk Pharma Ltd, Novartis Pharma K.K., Eli Lilly Japan K.K., Sanwa Kagaku Kenkyusho Co., Ltd, Daiichi Sankyo Co., Ltd, Takeda Pharmaceutical Co., Ltd, MSD K.K., Dainippon Sumitomo Pharma Co., and Kowa Co., Ltd and research funding from Nippon Boehringer Ingelheim Co., Ltd, Pfizer Japan, Inc., Mochida Pharmaceutical Co., Ltd, Sanofi K.K., Novo Nordisk Pharma Ltd, Novartis Pharma K.K., Sanwa Kagaku Kenkyusho Co., Ltd, Terumo Corp., Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd, Takeda Pharmaceutical Co., Ltd, MSD K.K., Shionogi & Co., Ltd, Dainippon Sumitomo Pharma Co., Kissei Pharmaceutical Co., Ltd, and AstraZeneca K.K. W Ohtsuka is an employee of Chugai Pharmaceutical Co., Ltd. D Watanabe is an employee of Sanofi K.K. H Suganami is an employee of Kowa Co., Ltd.

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Affiliation

Yukio Tanizawa†1 MD PhD, Kohei Kaku2 MD PhD, Eiichi Araki3 MD PhD, Kazuyuki Tobe4 MD PhD, Yasuo Terauchi5 MD PhD, Kazunori Utsunomiya6 MD PhD, Yasuhiko Iwamoto7 MD PhD, Hirotaka Watada8 MD PhD, Wataru Ohtsuka9, Daisuke Watanabe10 PhD, Hideki Suganami11 PhD & for the Tofogliflozin 004 and 005 Study group † Author for correspondence 1 Yamaguchi University Graduate School of Medicine, Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan Tel: +81 836 22 2250 (office); Fax: +81 836 22 2256; E-mail: [email protected] 2 Kawasaki Medical School, Department of Internal Medicine, Kurashiki, Japan 3 Kumamoto University, Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto, Japan 4 University of Toyama, The First Department of Internal Medicine, Toyama, Japan 5 Yokohama City University, Graduate School of Medicine, Department of Endocrinology and Metabolism, Yokohama, Japan 6 Jikei University School of Medicine, Department of Internal Medicine, Division of Diabetes, Metabolism and Endocrinology, Tokyo, Japan 7 Tokyo Women’s Medical University School of Medicine, Tokyo, Japan 8 Juntendo University Graduate School of Medicine, Department of Endocrinology & Metabolism, Tokyo, Japan 9 Chugai Pharmaceutical Co., Ltd, Clinical Research Planning Department, Tokyo, Japan 10 Sanofi K.K., Research & Development, Clinical Sciences & Operations, Biostatistics & Programming, Biostatistics, Tokyo, Japan 11 Kowa Co., Ltd, Clinical Data Science Department, Biostatistics Section, Tokyo, Japan