Efficacy and safety of luseogliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, placebo-controlled, phase II study.

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Efficacy and safety of luseogliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a 12week, randomized, placebo-controlled, phase II study a

b

c

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Yutaka Seino , Takashi Sasaki , Atsushi Fukatsu , Soichi Sakai & Yoshishige Samukawa a

Kansai Electric Power Hospital OsakaJapan

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Jikei University School of Medicine TokyoJapan

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Yachiyo Hospital AichiJapan

d

d

Taisho Pharmaceutical Co. Ltd TokyoJapan Published online: 26 May 2015.

Click for updates To cite this article: Yutaka Seino, Takashi Sasaki, Atsushi Fukatsu, Soichi Sakai & Yoshishige Samukawa (2014) Efficacy and safety of luseogliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, placebocontrolled, phase II study, Current Medical Research and Opinion, 30:7, 1219-1230 To link to this article: http://dx.doi.org/10.1185/03007995.2014.901943

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Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.901943

Vol. 30, No. 7, 2014, 1219–1230

Article FT-0031.R1/901943 All rights reserved: reproduction in whole or part not permitted

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Original article Efficacy and safety of luseogliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, placebo-controlled, phase II study

Yutaka Seino

Abstract

Kansai Electric Power Hospital, Osaka, Japan

Takashi Sasaki Jikei University School of Medicine, Tokyo, Japan

Atsushi Fukatsu

Objective: Luseogliflozin is a novel sodium glucose cotransporter 2 inhibitor for type 2 diabetes mellitus (T2DM) treatment. An exploratory Phase II study was conducted to assess the efficacy and safety of several doses of luseogliflozin in Japanese T2DM patients.

Yachiyo Hospital, Aichi, Japan

Soichi Sakai Yoshishige Samukawa Taisho Pharmaceutical Co. Ltd, Tokyo, Japan Address for correspondence: Soichi Sakai, Taisho Pharmaceutical Co. Ltd, 3-24-1, Takada, Toshima-ku, Tokyo, 170-8633, Japan. Tel.: +81 3 3985 1307; Fax: +81 3 3985 0650; [email protected] Keywords: Japanese – Luseogliflozin – Monotherapy – Phase II clinical study – Placebo – Sodium glucose cotransporter 2 (SGLT2) inhibitor – Type 2 diabetes mellitus Accepted: 3 March 2014; published online: 19 March 2014 Citation: Curr Med Res Opin 2014; 30:1219–30

Patients and methods: Japanese T2DM patients aged 20–74 years with hemoglobin A1c (HbA1c) of 6.9–10.5%, fasting plasma glucose (FPG) 126 mg/dL and on diet therapy were randomized in a double-blind manner to receive luseogliflozin (0.5, 2.5, or 5 mg) or placebo once daily for 12 weeks (n ¼ 61, 61, 61, and 56, respectively). The primary endpoint was the change in HbA1c from baseline to end of treatment. Other endpoints included FPG, 2 h postprandial plasma glucose (PPG) in a meal tolerance test (MTT), and body weight. Drug safety was also assessed. Trial registration: Japan Pharmaceutical Information Center (identifier: JapicCTI-090908). Results: Changes in HbA1c from baseline to end of treatment were 0.36, 0.62, and 0.75% in the 0.5, 2.5, and 5 mg luseogliflozin groups, respectively, versus þ0.06% in the placebo group (all P50.001). The reductions in FPG and 2 h-PPG in the MTT were also significantly greater in the luseogliflozin groups (all P50.01) without increases in insulin levels from baseline. Luseogliflozin reduced body weight at all doses. There were no significant differences in the incidences of adverse events among groups. Most adverse events were mild in severity. There were no serious adverse events. Conclusions: Although this was a small-scale study with a short duration, all tested doses of luseogliflozin significantly improved glycemic control, reduced body weight, and were well tolerated in Japanese T2DM patients over the 12-week treatment period.

Introduction Diabetes is thought to affect more than 371 million people worldwide, of whom about 90% have type 2 diabetes mellitus (T2DM)1. Although several oral antidiabetic drugs are used to treat type 2 diabetes, the risk of hypoglycemia, weight gain and insufficient efficacy may limit their use in some patients2. ! 2014 Informa UK Ltd www.cmrojournal.com

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Dipeptidyl peptidase-4 DPP4 inhibitors are widely used in Japan, and it is possible to achieve good glycemic control without hypoglycemia using this class of drugs3–5. However, although patient weight does not usually change when using DPP4 inhibitors, deteriorations in glycemic control may occur with weight gain6. Therefore, it is essential that novel drugs that overcome these problems are investigated as potential therapies for T2DM. The renal proximal tubules reabsorb most of the glucose present in the renal filtrate, and less than 1% of glucose in the renal filtrate is ultimately excreted in urine. Sodium glucose cotransporter 2 (SGLT2), which is primarily expressed in the proximal tubule7, is responsible for about 90% of glucose reabsorption in the kidney8,9. Animal studies have also shown that inhibition or deletion of SGLT2 promotes urinary glucose excretion and reduces hyperglycemia10–12, confirming the role of the kidney and SGLT2 in maintaining glucose homeostasis. These properties of SGLT2 have therefore prompted the development of SGLT2 inhibitors as novel treatments for T2DM13–15. Because SGLT2 activity is independent of insulin and this transporter is not expressed in either pancreatic b cells or insulin-sensitive tissues, SGLT2 inhibitors improve glycemic control in an insulinindependent manner16. Luseogliflozin [TS-071; (1S)-1,5-anhydro-1-[5-(4ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol hydrate] is a novel SGLT2 inhibitor currently under development for the treatment of T2DM. Preclinical studies have shown that luseogliflozin is a specific and selective SGLT2 inhibitor, and that it enhanced urinary glucose excretion in a dose-dependent manner in animal studies17,18. Luseogliflozin improved glucose tolerance without enhancing insulin secretion in Zucker fatty rats, and reduced hyperglycemia in streptozotocin-induced diabetic rats and db/db mice18. Thus, luseogliflozin ameliorated hyperglycemia without increasing insulin secretion in animal models of diabetes characterized by moderate defects in insulin secretion. However, the effects of luseogliflozin on hyperglycemia and insulin secretion in clinical settings have not been investigated in detail. In one clinical study, single and multiple doses of luseogliflozin dose dependently increased urinary glucose excretion without causing hypoglycemia in healthy Japanese males19. Additionally, the administration of luseogliflozin for 7 days significantly increased urinary glucose excretion and decreased plasma glucose levels in Japanese patients with T2DM20. However, these studies were too short to examine the effects on hemoglobin A1c (HbA1c) or adequately assess safety. The prevalence of diabetes in the Western Pacific region, including Japan, is higher than that in any other regions1. Japanese patients with T2DM exhibit more severe impairments in insulin secretion than Europeans 1220


and Americans, and develop diabetes with only slight worsening of obesity21. Therefore, it is important to investigate whether the SGLT2 inhibitor luseogliflozin, which reduces plasma glucose levels in an insulin-independent manner, is effective in Japanese T2DM patients with impaired insulin secretion. The results are expected to contribute to clinical practice in Japan and will be helpful to clarify the mechanism of action of SGLT2 inhibitors. Therefore, the purpose of the present study was to examine the efficacy and safety of several doses of luseogliflozin in Japanese patients with T2DM administered for 12 weeks in clinical settings. We also investigated the effect of luseogliflozin on insulin secretion by assessing post-meal insulin secretion in Japanese patients with T2DM.

Patients and methods Eligibility criteria Japanese outpatients with T2DM diagnosed according to the guidelines proposed by the Japan Diabetes Society22 were eligible if they met the following criteria: HbA1c 6.9–10.5% at Weeks -4 and -1, with a maximum change of 1.0% between these times; fasting plasma glucose (FPG) 126 mg/dL; prescribed with stable diet therapy 8 weeks before Week -4; and age 20–74 years. The exclusion criteria included the following: insulin-dependent state; diabetes other than type 2 diabetes; the presence of an endocrine disease likely to affect blood glucose; complications of renal disorders (serum creatinine level exceeding the upper limit of the reference range); history of chronic renal disorder or nephrectomy/renal transplantation; complication of or repeated urinary tract infection; clinically evident hepatic disorder (e.g., alanine aminotransferase or aspartate aminotransferase levels 2.5 times the upper limit of the reference range); complications of serious gastrointestinal disorder, serious cardiac disorder, or severe diabetic microangiopathy; and complication or history of malignant tumor; serious allergic disposition; use of oral antidiabetic drugs/insulin within 8 weeks before Week -4; use of an investigational drug 12 weeks before Week -4; past use of luseogliflozin; heavy alcohol consumption (average consumption of pure alcohol 4100 mL/day); pregnant or breast feeding; or were deemed by the investigator to be unsuitable for any other reason. All of the patients provided written informed consent before enrollment.

Study design and treatments This was a Phase II, randomized, placebo-controlled, double-blind, parallel-group study performed at 40 institutions distributed throughout Japan between April 2009 www.cmrojournal.com ! 2014 Informa UK Ltd



and November 2009. The study consisted of a 4 week, untreated observation period, in which patient eligibility was assessed and confirmed, followed by a 12-week treatment period. Visits were scheduled at Weeks -4 and -1 (observation period), and at Weeks 0, 2, 4, 8, and 12 in the treatment period. Patients were randomly allocated to one of four groups (0.5, 2.5, or 5 mg luseogliflozin or placebo) in a 1:1:1:1 ratio. The procedure of allocation and procedures implemented to maintain blinding are summarized in Supplementary appendix 1. The doses of luseogliflozin were chosen based on the safety, pharmacokinetic, and pharmacodynamic data of earlier Phase I studies in healthy Japanese males19. The study drugs were taken orally, once daily before breakfast. In addition, the patients were to continue their prescribed diet therapy, which was planned for the individual patients at each institution, for the duration of the study. The prescribed number of calories for diet therapy was not to be changed after Week -4. Compliance with these treatments was assessed at each visit (Supplementary appendix 1). If hypoglycemic symptoms appeared, glucose was to be administered orally or intravenously depending on the symptoms. Oral antidiabetic drugs, insulin, corticosteroids (except for topical use), intravenous fluids containing sugars, and other investigational drugs were prohibited for the entire study duration (observation and treatment periods). However, drugs to treat concomitant disorders (e.g., antidyslipidemic/antihypertensive drugs) could be continued if these drugs were being used from before Week -4, and if their doses and types were not to be changed during the study. The study was conducted according to Good Clinical Practice and the Declaration of Helsinki, and was approved by the institutional review boards at each participating medical institution. This study was registered with the Japan Pharmaceutical Information Center (identifier: JapicCTI-090908).

Study endpoints and measurements The primary efficacy endpoint was the change in HbA1c from baseline to the end of treatment. Secondary efficacy endpoints included FPG, postprandial plasma glucose (PPG), insulin, intact proinsulin, C-peptide immunoreactivity (CPR), glucagon, glycosylated albumin, body weight, and urinary glucose. HbA1c was measured in Japan Diabetes Society (JDS) units, which were generally used in Japanese clinical practice at the time of this study. The JDS values were converted to National Glycohemoglobin Standardization Program (NGSP) units using the certified equation HbA1c (NGSP) for Japanese patients23: (%) ¼ 1.02 HbA1c (JDS) (%) þ 0.25%. ! 2014 Informa UK Ltd www.cmrojournal.com

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Meal tolerance tests were performed at Weeks 0 (before study drug administration) and 12 using a test meal provided by the sponsor (516 kcal; protein 19.2%, lipids 19.7%, carbohydrates 58.4%). After an overnight fast, the patients attended the medical institution at 8:00– 11:00 h, and consumed a test meal for 10 min (5 min). Blood samples were collected before and at 0.5, 1, and 2 h after the meal to measure plasma glucose, insulin, CPR, and glucagon. Urine was pooled from the start of the meal to 2 h after the meal to measure urinary glucose. The allocated study drug was to be taken within 30 min before the meal. Efficacy variables were measured at an independent laboratory (Mitsubishi Chemical Medience Corp., Tokyo, Japan). Safety outcomes included adverse events (AEs), clinical laboratory variables, and vital signs, which were assessed at every visit, and 12-lead electrocardiography, which was performed at Weeks -4, 0, 2, and 12. AEs were coded using the Japanese version of the Medical Dictionary for Regulatory Activities, version 12.1, in terms of system organ class and preferred term. AEs were classified in terms of severity (mild, moderate, or severe) and possible association with the study drug (definitely related, probably related, possibly related, not related, or unknown).

Statistical analyses Based on a study of another SGLT2 inhibitor24, we assumed that the difference between the mean decreases in HbA1c in the 2.5 mg luseogliflozin and placebo groups was 0.42%. With a standard deviation of 0.7%, two-sided significance level of 5%, and statistical power of 80%, at least 45 patients were needed for these two groups. We therefore planned to enroll about 50 patients per treatment group to allow for dropouts and exclusions. Efficacy analyses were conducted in the full analysis set, which consisted of all patients who took at least one dose of the study drug and in whom efficacy variables were examined at least once. Safety analyses were conducted in the safety analysis set, which consisted of all patients who took at least one dose of the study drug and in whom the safety variables were measured at least once. Baseline characteristics were compared among the four groups using 2 tests and analysis of variance. A significance level of 15% (two sided) was used to examine the heterogeneity of patient characteristics. For primary and secondary efficacy endpoints, the changes from baseline to each point of evaluation and to the end of treatment were calculated. Missing data at the end of treatment were imputed using the last observation carried forward method. The unrestricted least significant difference method was applied to calculate the least squares mean and 95% confidence interval for the changes Efficacy and safety of luseogliflozin monotherapy Seino et al.

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in efficacy variables in each group, as well as differences between each luseogliflozin group and the placebo group. For these analyses, a significance level of 5% (two-sided) was used. Changes in clinical/laboratory safety variables were determined as described for the efficacy variables. All statistical analyses were performed using SAS version 9.1.3 (SAS Inc., Cary, NC, USA).

Results Downloaded by [Stockholm University Library] at 11:33 12 August 2015

Patient characteristics As shown in Figure 1, of 297 patients who provided informed consent, 239 were randomized into the four groups, with 56–61 patients per group. Overall, 236 patients received the study drug and 232 completed the 12 week study. The baseline characteristics of the patients are presented in Tables 1–3. The four groups were generally similar in terms of baseline characteristics, although there was some evidence for differences at P50.15 among the groups for some factors, including glycosylated albumin, fasting insulin, fasting intact proinsulin, HOMA-R, and HOMA-b. The mean age and HbA1c ranged from 55.2 years to 58.3 years and from 7.88% to 8.16%, respectively.

Glycemic control HbA1c significantly decreased from baseline to the end of treatment in the 0.5, 2.5, and 5 mg groups compared with the placebo group (0.36%, 0.62%, and 0.75%, respectively, vs. þ0.06%; all, P50.001; Table 2 and Figure 2a). The magnitude of the reduction tended to be greater in the 2.5 and 5 mg groups than in the 0.5 mg group. The mean decrease from baseline in HbA1c was significantly lower at Weeks 4, 8, and 12 in each of the luseogliflozin groups than in the placebo group (all, P50.001), and at Week 2 in the 5 mg luseogliflozin group (P ¼ 0.015). The change in HbA1c from baseline to the end of treatment in each luseogliflozin group tended to be greater in patients with higher baseline HbA1c levels, although the numbers of subjects in these subgroups were low (Supplementary table 1). Overall, 8.6% (5/58), 15.0% (9/60), and 20.3% (12/59) of patients achieved HbA1c 57.0% at the end of treatment in the 0.5, 2.5, and 5 mg luseogliflozin groups, respectively, compared with 7.5% (4/53) in the placebo group. Consistent with the changes in HbA1c, the decreases in FPG from baseline to each visit were significantly greater in all of the luseogliflozin groups than in the placebo group (Figure 2c; all P50.05 for 0.5 mg luseogliflozin; all P50.001 for 2.5 or 5 mg luseogliflozin), as were the changes from baseline to the end of treatment (Table 2). Notably, the reductions in FPG were apparent by Week 2

Provided informed consent n = 297

Withdrawn before randomization n = 58 • Did not satisfy eligibility criteria n = 54 • Withdrew consent n = 3 • Other reason n = 1

Randomized to treatment n = 239

Placebo n = 56

0.5 mg n = 61

Did not receive study drug n=2 Included in efficacy and safety analysis sets n = 54

Completed the study n = 52

5 mg n = 61

Included in efficacy and safety analysis sets n = 61


Did not receive study drug n=1


Discontinued n=2 • Adverse event (withdrew consent) n = 1 • Lost to follow up n=1

2.5 mg n = 61

Discontinued n=1 • Adverse event (withdrew consent) n=1


Discontinued n=1 • Adverse event (withdrew consent) n=1



Figure 1. Patient disposition.

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Table 1. Patient characteristics (full analysis set).


Variable

P*

Luseogliflozin

Sex Male Female Age (years) Body weight (kg) BMI (kg/m2) Duration of diabetes (years) Prior treatment for diabetesx HbA1c (%) FPG (mg/dL) 2 h-PPG (mg/dL) Fasting insulin (mU/mL) SBP (mmHg) DBP (mmHg)

Placebo n ¼ 54

0.5 mg n ¼ 60

2.5 mg n ¼ 61

5 mg n ¼ 61

40 (74.1%) 14 (25.9%) 57.6 (11.0) 68.3 (13.4) 25.2 (4.26) 7.30 (6.43) 9 (16.7%) 7.88 (0.72) 153.1 (24.8) 235.1 (44.7) 8.7 (7.5) 123.0 (14.6) 72.9 (10.4)

41 (68.3%) 19 (31.7%) 55.2 (10.1) 69.7 (13.7) 25.4 (3.54) 4.90 (4.49) 11 (18.3%) 8.16 (0.93) 158.7 (28.8) 248.4 (52.4) 7.8 (4.9) 125.2 (12.4) 75.0 (9.9)

35 (57.4%) 26 (42.6%) 58.3 (9.4) 65.5 (12.2) 24.8 (3.56) 6.15 (6.50 17 (27.9%) 8.07 (0.90) 158.1 (30.3) 242.0 (64.4) 6.1 (3.5) 124.6 (13.2) 74.4 (9.2)

44 (72.1%) 17 (27.9%) 56.8 (9.3) 66.3 (12.4) 24.5 (3.21) 5.77 (5.55) 16 (26.2%) 8.16 (0.96) 159.9 (34.7) 254.6 (59.8) 6.0 (3.6) 126.8 (14.3) 75.6 (10.5)

0.209y 0.335z 0.275z 0.487z 0.174z 0.369y 0.309z 0.640z 0.280z 0.010z – –

Values are means (standard deviation) or n (%). BMI, body mass index; HbA1c, hemoglobin A1c; FPG, fasting plasma glucose; PPG, postprandial plasma glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure. *A significance level of P50.15 (two-sided) was taken to indicate heterogeneity among the study groups. y2 test. zAnalysis of variance. xSubjects who were receiving treatment for diabetes 8 weeks before Week -4 (start of the observation period). Safety analysis set.

Table 2. Changes in efficacy variables from baseline to the end of treatment (last observation carried forward, full analysis set). Variable

HbA1c (%) Baseline Change Difference vs. placebo FPG (mg/dL) Baseline Change Difference vs. placebo 2 h PPG (mg/dL) n at EOTx Baseline Change Difference vs. placebo AUC0–2h glucose (mgh/dL) n at EOTx Baseline Change Difference vs. placebo Fasting insulin (mU/mL) n at EOTx Baseline Change Difference vs. placebo 2 h insulin (mU/mL) n at EOTx Baseline Change Difference vs. placebo AUC0–2h insulin (mUh/mL) n at EOTx Baseline Change

Pbaseline*

Luseogliflozin Placebo n ¼ 54

7.88 (0.72) 0.06 (0.1, 0.2) –

0.5 mg n ¼ 60

2.5 mg

n ¼ 61

5 mg n ¼ 61

8.16 (0.93) 0.36 (0.5, 0.2)y 0.42 (0.6, 0.2)

8.07 (0.90) 0.62 (0.8, 0.5)y 0.68 (0.9, 0.5)

8.16 (0.96) 0.75 (0.9, 0.6)y 0.82 (1.0, 0.6)

0.309

153.1 (24.8) 0.1 (7, 7) –

158.7 (28.8) 13.7 (20, 7)z 13.8 (23, 4)

158.1 (30.3) 24.6 (31, 18)y 24.7 (34, 15)

159.9 (34.7) 26.9 (33, 21)y 27.0 (36, 18)

0.640

52 235.1 (44.7) 0.8 (10, 12) –

59 248.4 (52.4) 36.0 (47, 26)y 36.8 (52, 21)

60 242.0 (64.4) 43.0 (53, 33)y 43.8 (59, 28)

61 254.6 (59.8) 59.0 (69, 49)y 59.9 (75, 45)

52 469 (63.7) 2.02 (18.1, 14.1) –

59 484 (75.4) 48.8 (63.9, 33.7)y 46.8 (68.9, 24.7)

60 483 (89.0) 72.3 (87.3, 57.3)y 70.3 (92.3, 48.3)

61 496 (83.3) 88.9 (104, 74.1)y 86.9 (109, 65.0)

52 8.68 (7.55) 1.17 (1.9, 0.4) –

59 7.75 (4.90) 0.56 (1.3, 0.1) 0.61 (0.4, 1.6)

60 6.08 (3.52) 1.06 (1.8, 0.4) 0.11 (0.9, 1.1)

61 6.00 (3.60) 1.09 (1.8, 0.4) 0.08 (0.9, 1.1)

52 33.49 (22.30) 0.54 (3.4, 4.5) –

59 38.19 (31.23) 6.03 (9.7, 2.4)z 6.57 (11.9, 1.2)

60 29.05 (19.07) 5.42 (9.1, 1.8)z 5.96 (11.3, 0.6)

61 31.68 (20.60) 6.27 (9.9, 2.7)z 6.81 (12.1, 1.5)

52 56.2 (38.7) 0.851 (4.80, 3.10)

59 57.9 (40.0) 2.20 (5.90, 1.51)

60 45.8 (22.5) 4.64 (8.32, 0.97)

61 48.6 (28.7) 3.95 (7.60, 0.31)

0.280

n/d

0.010

0.194

n/d

(continued )

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Table 2. Continued. Variable


Difference vs. placebo Body weight (kg) Baseline Change Difference vs. placebo Urinary glucose (g/2 h)k n at EOTx Baseline Change Glycosylated albumin (%) Baseline Change Intact proinsulin (pmol/L) n at EOTx Baseline Change HOMA-R n at EOTx Baseline Change HOMA-b (%) n at EOTx Baseline Change Intact proinsulin/insulin ratio n at EOTx Baseline Change

Pbaseline*

Luseogliflozin Placebo n ¼ 54

0.5 mg n ¼ 60

2.5 mg

n ¼ 61

5 mg n ¼ 61

–

1.34 (6.76, 4.07)

3.79 (9.19, 1.60)

3.10 (8.48, 2.27)

68.30 (13.41) 0.35 (0.7, 0.0) –

69.70 (13.69) 0.81 (1.2, 0.5) 0.46 (1.0, 0.1)

65.54 (12.22) 2.01 (2.4 1.7)y 1.66 (2.2, 1.1)

66.27 (12.42) 2.08 (2.4, 1.7)y 1.73 (2.2, 1.2)

57 3.17 (4.59) 4.24 (3.2, 5.2)y

58 2.84 (3.63) 7.51 (6.5, 8.5)y

52 2.50 (2.27) 0.11 (0.9, 1.2)

59 2.92 (2.55) 8.67 (7.7, 9.7)y

0.275

0.771

20.77 (3.13) 0.33 (0.3, 0.9)

21.75 (3.79) 1.64 (2.2, 1.1)y

21.92 (3.62) 2.86 (3.4, 2.3)y

22.46 (3.89) 3.37 (3.9, 2.8)y

53 10.25 (7.28) 1.16 (2.0, 0.3)

59 10.04 (6.59) 0.69 (1.5, 0.1)

61 7.04 (4.34) 1.10 (1.9, 0.3)

61 8.70 (6.63) 2.36 (3.1, 1.6)z

0.021

52 3.45 (3.68) 0.48 (0.8, 0.1)

59 3.02 (1.84) 0.44 (0.8, 0.1)

60 2.42 (1.67) 0.75 (1.1, 0.4)

61 2.34 (1.37) 0.72 (1.0, 0.4)

0.029

52 36.0 (31.1) 4.4 (8, 1) 52 0.20 (0.11) 0.01 (0.0, 0.0)

0.096

59 31.6 (24.0) 2.0 (1, 5)z

60 24.5 (15.0) 2.5 (1, 6)z

61 25.0 (17.9) 1.9 (1, 5)z

0.017

59 0.21 (0.14) 0.00 (0.0, 0.0)

60 0.19 (0.11) 0.01 (0.0, 0.0)

61 0.22 (0.12) 0.01 (0.0, 0.0)

0.529

Values are means (standard deviation) for the baseline value or the least squares means (95% confidence interval) for the change from baseline and the difference versus placebo. HbA1c, hemoglobin A1c; FPG, fasting plasma glucose; PPG, postprandial plasma glucose; EOT, end of treatment; AUC0–2h, area under the concentration–time curve for 0–2 h during the meal tolerance test; n/d, no data; HOMA-R, homeostasis model assessment of insulin resistance; HOMA-b, homeostasis model assessment of b cell function. *P-values are given for baseline values (analysis of variance). A significance level of P50.15 (two-sided) was taken to indicate heterogeneity among the study groups. yP50.001 vs. placebo. zP50.05 vs. placebo. xThe number of patients for whom at least one value was measured after starting treatment is shown. kUrine samples were collected from before to 2 h after the meal, and were pooled to measure urinary glucose. Data are shown for patients who underwent the meal tolerance test at baseline and at Week 12 (end of treatment).

in all luseogliflozin groups, and the changes tended to be greater in the 2.5 and 5 mg groups than in the 0.5 mg group.

Meal tolerance test Figure 3 shows the changes in glucose and insulin levels during the meal tolerance test. There were minimal changes in plasma glucose and serum insulin levels at each time-point during the meal tolerance test from baseline to the end of treatment in the placebo group. By contrast, FPG and PPG decreased from baseline to the end of treatment in each of the luseogliflozin groups. The decreases in FPG and PPG were significantly greater in the luseogliflozin groups than in the placebo group (P ¼ 0.004 for before the meal in the 0.5 mg group; P50.001 for other groups and times, except at 0.5 h after the meal in the 0.5 mg group; Figure 3a and Table 2). 1224


The magnitudes of the decreases in plasma glucose levels in the luseogliflozin groups tended to increase over time after the meal. The plasma glucose AUC0–2h also decreased significantly from baseline to the end of treatment in each of the luseogliflozin groups compared with placebo (all P50.001). At baseline, serum insulin levels reached a plateau at 1 h after the meal and reached a peak at 2 h after the meal in all four groups. Meanwhile, 2 h insulin levels were lower at the end of treatment than at baseline in the luseogliflozin groups, consistent with the changes in plasma glucose levels. At the end of treatment, the insulin levels reached a peak at 1 h after the meal, which was earlier than that at baseline. The decreases in 2 h insulin levels were significantly greater in the luseogliflozin groups than in the placebo group (all P50.05; Figure 3b and Table 2). However, the changes in serum insulin levels at 0.5 and 1 h after the meal were small or non-existent in each of the luseogliflozin groups, www.cmrojournal.com ! 2014 Informa UK Ltd


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Table 3. Changes in clinical/laboratory variables from baseline to the end of treatment (safety analysis set). Variable

Placebo


n ¼ 54 SBP (mmHg) Baseline Change DBP (mmHg) Baseline Change Urine volume (mL/2 h)y n at EOT Baseline Change RBC count (104/mL) Baseline Change Hemoglobin (g/dL) Baseline Change Hematocrit (%) Baseline Change BUN (mg/dL) Baseline Change Uric acid (mg/dL) Baseline Change Creatinine (mg/dL) Baseline Change Sodium (mEq/L) Baseline Change Phosphorus (mg/dL) Baseline Change ALT (IU/L) Baseline Change AST (IU/L) Baseline Change g-GTP (IU/L) Baseline Change Triglycerides (mg/dL) Baseline Change Free fatty acids (mEq/L) Baseline Change

Luseogliflozin 0.5 mg n ¼ 60

2.5 mg n ¼ 61

5 mg n ¼ 61

123.0 (14.6) 1.0 (4, 2)

125.2 (12.4) 3.6 (6, 1)

124.6 (13.2) 6.1 (9, 3)*

126.8 (14.3) 6.6 (9, 4)*

72.9 (10.4) 0.0 (2, 2)

75.0 (9.9) 1.3 (3, 1)

74.4 (9.2) 2.8 (5, 1)

75.6 (10.5) 3.0 (5, 1)

52 219.77 (164.03) 23.13 (17.0, 63.2)

59 221.85 (229.28) 51.47 (13.8, 89.1)

60 203.32 (147.29) 57.73 (20.4, 95.1)

455.2 (39.1) 2.8 (3, 8)

458.7 (37.9) 17.4 (12, 23)z

455.3 (36.1) 21.2 (16, 26)z

459.3 (37.0) 23.1 (18, 28)z

14.40 (1.11) 0.23 (0.1, 0.4)

14.13 (1.57) 0.66 (0.5, 0.8)z

14.22 (1.13) 0.85 (0.7, 1.0)z

14.39 (1.00) 0.92 (0.8, 1.1)z

42.39 (3.17) 0.56 (0.0, 1.1)

41.58 (4.28) 2.03 (1.5, 2.5)z

41.81 (3.20) 2.52 (2.0, 3.0)z

42.39 (2.78) 2.86 (2.4, 3.4)z

14.0 (3.0) 1.0 (2, 0)

13.3 (3.4) 0.7 (0, 1)*

14.2 (4.0) 0.8 (0, 1)*

61 230.33 (178.48) 79.08 (42.1, 116.1)*

13.7 (2.5) 1.4 (1, 2)z

5.34 (1.30) 0.17 (0.4, 0.0)

5.29 (1.09) 0.43 (0.6, 0.2)

5.09 (1.49) 0.63 (0.8, 0.5)*

5.08 (1.29) 0.57 (0.8, 0.4)*

0.712 (0.129) 0.004 (0.02, 0.01)

0.694 (0.147) 0.002 (0.02, 0.01)

0.676 (0.149) 0.003 (0.01, 0.02)

0.710 (0.150) 0.012 (0.00, 0.03)

139.3 (1.6) 0.0 (0, 0)

139.5 (1.6) 0.2 (0, 1)

139.2 (1.7) 0.3 (1, 0) 3.31 (0.46) 0.05 (0.1, 0.0)

139.1 (1.7) 0.0 (0, 0) 3.30 (0.46) 0.03 (0.1, 0.1)

3.28 (0.50) 0.05 (0.1, 0.2)

3.25 (0.41) 0.14 (0.0, 0.2)*

28.1 (18.4) 0.2 (2, 2)

26.5 (16.3) 1.8 (4, 0)

23.2 (11.2) 2.3 (4, 0)

24.5 (16.0) 3.3 (5, 1)*

24.8 (9.3) 0.6 (1, 2)

23.2 (9.4) 0.8 (2, 1)

22.9 (6.9) 0.7 (2, 1)

22.6 (8.4) 0.6 (2, 1)

46.5 (38.4) 2.7 (1, 7)

45.5 (34.3) 1.9 (6, 2)

40.9 (31.0) 4.2 (8, 0)*

43.0 (31.4) 7.1 (11, 3)z

170.0 (189.2) 9.2 (16, 34)

173.7 (106.4) 12.3 (36, 12)

150.2 (106.6) 13.7 (37, 10)

160.4 (146.3) 29.0 (53, 5)*

0.556 (0.166) 0.043 (0.01, 0.10)

0.555 (0.191) 0.048 (0.01, 0.10)

0.532 (0.205) 0.103 (0.05, 0.16)*

0.547 (0.192) 0.012 (0.07, 0.05)

Values are means (standard deviation) or least-squares mean (95% confidence interval). SBP, systolic blood pressure; DBP, diastolic blood pressure; EOT, end of treatment; RBC, red blood cell; BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate aminotransferase; g-GTP, g-glutamyl transpeptidase. *P50.05 vs. placebo. yUrine samples were collected from before eating to 2 h after the meal and were pooled to measure urinary glucose. The number of patients for whom at least one value was measured after starting treatment is shown. zP50.001 vs. placebo.

and were not statistically significant compared with the placebo group. In addition, as expected from its mechanism of action, luseogliflozin dose dependently and significantly increased urinary glucose excretion relative to baseline values and the values in the placebo group (Table 2). ! 2014 Informa UK Ltd www.cmrojournal.com

Body weight Body weight decreased from baseline in all of the luseogliflozin groups as early as Week 2 and continued to decline for the entire duration of the study (Figure 2d). The reductions at the end of treatment (Table 2) were significantly Efficacy and safety of luseogliflozin monotherapy Seino et al.

1225

†

†

†

*

0.0 −0.2 −0.4 −0.6 −0.8 −1.0

2

4

8 Time (weeks)

Placebo 2.5 mg luseogliflozin

(c) Change in FPG from baseline (mg/dL)

†

12

EOT

0.5 mg luseogliflozin 5 mg luseogliflozin

10 5

*†

0

*†

*†

*†

*†

−5 −10 −15 −20 −25 −30 −35 0

2

4

8 Time (weeks)

12

EOT

0.5 mg luseogliflozin

(b) Placebo-adjusted change in HbA1c from baseline to EOT (%)

Change in HbA1c from baseline (%)

0.2

0



Placebo 2.5 mg luseogliflozin

(a)

July 2014


5 mg luseogliflozin

0.0

−0.4

−0.8

−1.2 Placebo 2.5 mg luseogliflozin

(d) Change in body weight from baseline (kg)



0.5

*†

0.0

*†

*†

†

†

12

EOT

−0.5 −1.0 −1.5 −2.0 −2.5 0

2

4

8 Time (weeks)

Figure 2. (a) Changes in HbA1c from baseline to each visit or end of treatment (EOT). *P ¼ 0.015 for 5 mg luseogliflozin vs. placebo; yP50.001 for all luseogliflozin groups vs. placebo. (b) Placebo-adjusted change in HbA1c from baseline to the EOT. (c) Changes in FPG from baseline to each visit or EOT. *P50.05 for 0.5 mg luseogliflozin vs. placebo; yP50.001 for 2.5 and 5 mg luseogliflozin vs. placebo. (d) Changes in body weight from baseline to each visit or EOT. *P50.05 for 0.5 mg luseogliflozin vs. placebo; yP50.001 for 2.5 and 5 mg luseogliflozin vs. placebo. Values are means standard error (a, c, and d) or least squares mean 95% confidence interval (b). All data are shown for the full analysis set. The last observation carried forward method was applied to data at the EOT. Differences between each luseogliflozin group and placebo were analyzed by the unrestricted least significant difference method. HbA1c, hemoglobin A1c; FPG, fasting plasma glucose.

greater in the 2.5 and 5 mg luseogliflozin groups than in the placebo group.

Adverse events The incidence of AEs ranged from 36.1% to 50.0% in each group, while that of adverse drug reactions (ADRs) ranged from 7.4% to 23.0% (Table 4). There were no significant differences in the incidences of AEs and ADRs among the four groups. Most AEs were classified as mild and none was classified as severe. There were no deaths during the study and there were no serious AEs. In one patient in each of the placebo, 0.5 mg, and 2.5 mg groups, the study drug was suspended and then discontinued because of AEs. The events in the luseogliflozin groups (diarrhea in the 0.5 mg group and penile ulceration in the 2.5 mg group) were classified as mild and the patients recovered. 1226


The most common AEs with an incidence of 3% in any luseogliflozin group are listed in Table 4. The most common ADRs, with an incidence of 3% in any luseogliflozin group, were increased b-N-acetyl-D-glucosaminidase (NAG), pollakiuria, and the presence of ketone bodies in urine. We also examined the incidence of AEs of special interest (hypoglycemia, urinary tract infections, genital infections, AEs related to pollakiuria, AEs related to renal function, and AEs related to volume depletion) (Table 4). Hypoglycemia occurred in one patient treated with 0.5 mg luseogliflozin. This patient reported feeling dizzy and having visual disturbances; these symptoms disappeared after eating. Urinary tract infection occurred in one patient in the 0.5 mg luseogliflozin group who experienced two episodes of cystitis, which resolved after treatment. Both events were considered possibly related to the study drug. Genital infections occurred in one patient in www.cmrojournal.com ! 2014 Informa UK Ltd


Baseline End of treatment Placebo

Plasma glucose (mg/dL)

(a) 300

*

100

5 mg luseogliflozin

†

†

†

†

†

†

†

†

†

0 0.5 1 2 Time after meal (h)

0

0.5 1 2 Time after meal (h)

0


0


Baseline End of treatment

(b) Serum insulin (µU/mL)


†

200

0



July 2014

Placebo

50



5 mg luseogliflozin

40 30

*

20

*

*

10 0 0


0


0


0


Figure 3. Plasma glucose (a) and insulin (b) levels during the meal tolerance tests performed at Week 0 and at the end of treatment (EOT). Values are means standard error. All data are shown for the full analysis set. The last observation carried forward method was applied to data at EOT. Changes from baseline and differences in the change from baseline to EOT between each luseogliflozin group and placebo were analyzed by the unrestricted least significant difference method. *P50.05 vs. placebo; yP50.001 vs. placebo.

each of the 2.5 mg (vulvitis) and 5 mg groups (vulvovaginal candidiasis), and were mild in severity. Regarding AEs related to volume depletion, thirst occurred in one patient in each of the 0.5 mg and 2.5 mg groups, but these events resolved without treatment. The incidence of AEs related to renal function was similar among the study groups.

Clinical and laboratory variables Table 3 shows the clinical and laboratory variables at baseline and the changes from baseline to the end of treatment. The reductions in systolic blood pressure from baseline to the end of treatment were significantly greater in the 2.5 and 5 mg groups than in the placebo group (both P50.05). The red blood cell count, hemoglobin, hematocrit, and blood urea nitrogen increased significantly from baseline to the end of treatment in all of the luseogliflozin groups versus the placebo group. However, the magnitudes of the increases were small and none of the patients had increases in these parameters that were judged as AEs. Urine volume increased in all of the luseogliflozin groups at the end of treatment from baseline, and the increase was significant in the 5 mg luseogliflozin group versus placebo. Liver enzymes, uric acid, and triglycerides tended to decrease in the luseogliflozin groups versus the placebo group, while free fatty acid levels tended to increase. There ! 2014 Informa UK Ltd www.cmrojournal.com

were no clinically meaningful changes in serum creatinine, electrolytes, or cystatin C (data not shown).

Discussion This study revealed that luseogliflozin monotherapy for 12 weeks significantly improved glycemic control (HbA1c, FPG, and PPG) and reduced body weight in Japanese patients with T2DM. The reduction in plasma glucose observed in this study was associated with the increase in urinary glucose excretion, and these effects tended to be greater at luseogliflozin doses of 2.5 or 5 mg than at 0.5 mg. The reductions in HbA1c and FPG were apparent within 2–4 weeks of starting treatment, and were maintained throughout the 12-week treatment period. Plasma glucose decreased rapidly, reaching a plateau at Week 2. This effect was consistent with the results of a prior clinical pharmacology study of luseogliflozin20, and seems to be a favorable aspect of its treatment of T2DM. The effects of SGLT2 inhibitors in Japanese T2DM patients, who often have impaired early phase insulin secretion after a meal, seem to have attracted considerable attention. The results of the meal tolerance tests performed in the present study are particularly intriguing. In the present study, the early phase insulin levels were not Efficacy and safety of luseogliflozin monotherapy Seino et al.

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July 2014

Table 4. List of adverse events (safety analysis set) defined according to the MedDRA.


Luseogliflozin

Any AE Any ADR Any SAE AEs leading to discontinuation Most common AEs by preferred term* Nasopharyngitis Diarrhea Increased NAG Pollakiuria Upper respiratory tract infection Headache Increased white blood cell count Pharyngitis Periodontitis Presence of ketone bodies in urine AEs of special interest Hypoglycemia Urinary tract infectionsy Genital infectionsz AEs related to pollakiuriax AEs related to renal functionk AEs related to volume depletionô

Placebo n ¼ 54

0.5 mg (n ¼ 60)

2.5 mg (n ¼ 61)

5 mg (n ¼ 61)

27 (50.0) 4 (7.4) 0 (0) 1 (1.9)

26 (43.3) 8 (13.3) 0 (0) 1 (1.7)

27 (44.3) 14 (23.0) 0 (0) 1 (1.6)

22 (36.1) 7 (11.5) 0 (0) 0 (0)

4 (7.4) 3 (5.6) 1 (1.9) 1 (1.9) 0 (0) 0 (0) 2 (3.7) 0 (0) 0 (0) 0 (0)

11 (18.3) 3 (5.0) 3 (5.0) 0 (0) 2 (3.3) 2 (3.3) 0 (0) 0 (0) 0 (0) 0 (0)

2 (3.3) 2 (3.3) 1 (1.6) 2 (3.3) 2 (3.3) 1 (1.6) 1 (1.6) 4 (6.6) 2 (3.3) 2 (3.3)

5 (8.2) 0 (0) 2 (3.3) 3 (4.9) 1 (1.6) 2 (3.3) 2 (3.3) 0 (0) 1 (1.6) 0 (0)

0 (0) 0 (0) 0 (0) 1 (1.9) 5 (9.3) 0 (0)

1 (1.7) 1 (1.7) 0 (0) 0 (0) 5 (8.3) 1 (1.7)

0 (0) 0 (0) 1 (1.6) 3 (4.9) 6 (9.8) 1 (1.6)

0 (0) 0 (0) 1 (1.6) 3 (4.9) 6 (9.8) 0 (0)

Values are n (%). AE, adverse event; ADR, adverse drug reaction; SAE, serious adverse event; NAG, b-N-acetyl-D-glucosaminidase. *Events with an incidence of 3% of patients in any luseogliflozin group. yCystitis. zVulvitis and vulvovaginal candidiasis. xPollakiuria, and increased urine output. kUrinary calculus, presence of cells in urine, increased NAG, pollakiuria, presence of blood in urine, presence of crystals in urine, presence of protein in urine, urinary retention, increased urinary b2-microglobulin, presence of red blood cells in urine, and presence of white blood cells in urine. ôThirst.

altered by luseogliflozin treatment. However, when we consider that the plasma glucose levels were reduced by luseogliflozin, the early phase insulin secretion seems to have improved. We also demonstrated that the plasma insulin levels measured 2 h after meal ingestion were decreased by luseogliflozin, probably because of the lower glucose levels. Taken together, these results suggest that luseogliflozin indirectly improved insulin secretion in Japanese patients with T2DM. Luseogliflozin monotherapy not only improved glycemic control but also reduced body weight. The reduction in body weight in the luseogliflozin groups was significant within 2 weeks of starting treatment and had not reached a plateau by Week 12. An increase in energy use and an increase in urine output were thought to contribute to its mechanism. Luseogliflozin also tended to improve blood pressure, uric acid, and liver function. Therefore, it seems likely that luseogliflozin may have some benefits on the metabolic profiles of T2DM patients. In this, the first 12 week study of luseogliflozin in patients with T2DM, all of the tested doses of luseogliflozin were well tolerated. Most of the AEs were classified as 1228


mild, and there were no deaths or serious AEs during the treatment period. As expected from the characteristics of SGLT2 inhibitors, luseogliflozin was associated with a low incidence of hypoglycemia. Because SGLT2 is not expressed in pancreatic b cells or insulin-sensitive tissues (e.g., liver and muscle), luseogliflozin is expected to work in an insulinindependent manner. In addition, SGLT2 inhibitors inhibit the reabsorption of about 30–50% of the filtered glucose load, avoiding hypoglycemia25. Only one episode of hypoglycemia occurred in our study, and it was classified as mild. Because the kidney is the target organ of luseogliflozin, the effects of luseogliflozin on renal function were assessed. In this study, although increases in markers of renal tubular disorders (e.g., increased NAG or increased urinary b2-microgloblin) were observed in the luseogliflozin groups, they were also observed in the placebo group. These increases were all classified as mild in severity. This means that luseogliflozin did not cause renal impairment or failure in this study. However, longer studies will be needed to assess the effects of luseogliflozin on kidney function. www.cmrojournal.com ! 2014 Informa UK Ltd



Increased urinary glucose is also associated with increased risk of genital and urinary tract infections during treatment with SGLT2 inhibitors26,27. Nevertheless, the incidence of these events was low, all events were classified as mild, and all resolved after appropriate treatment in this study. In this study, the presence of ketone bodies in urine was observed in two patients who were treated with 2.5 mg luseogliflozin. It is possible that the increase in urinary glucose excretion during treatment with luseogliflozin might induce caloric loss and lipolysis. Further studies are needed to examine the changes in serum ketone levels during treatment with luseogliflozin. The slight increases in red blood cell count, hemoglobin, hematocrit, and blood urea nitrogen in the luseogliflozin groups were possibly due to volume depletion. The increase in urinary glucose excretion might cause osmodiuresis, resulting in increases in these parameters. The main limitations of this study were the short study duration and the small sample size, which might explain the low incidence of AEs of special interest. Therefore, further studies are necessary to fully evaluate the tolerability of luseogliflozin. Several longer and larger studies including other doses were recently completed, and the results will provide further insight into the safety profile of luseogliflozin.

Conclusions In conclusion, this was the first randomized controlled trial examining the efficacy and safety of luseogliflozin in Japanese patients with T2DM. Monotherapy with luseogliflozin for 12 weeks was associated with marked improvements in glycemic control and reductions in body weight, and was well tolerated in Japanese patients with T2DM.

Transparency Declaration of funding Luseogliflozin is being developed by Taisho Pharmaceutical Co. Ltd. This study was supported by Taisho Pharmaceutical Co. Ltd. Declaration of financial/other relationships Y.Se. has disclosed that he has received consultancy fees or lecture fees from Sanofi, Novo Nordisk, Eli Lilly and Company, GlaxoSmithKline, Astellas Pharma, Takeda Pharmaceuticals, Boehringer Ingelheim, Johnson & Johnson, Becton Dickinson and Company, AstraZeneca, and Taisho Pharmaceutical Co. Ltd. T.S. has disclosed that he has received joint research funds from Canon Inc. and consultancy fees from Taisho Pharmaceutical Co. Ltd. A.F. has disclosed that he has received consultancy fees from Taisho Pharmaceutical Co. Ltd. S.S. and Y.Sa. have disclosed that they are employees of Taisho Pharmaceutical Co. Ltd.

! 2014 Informa UK Ltd www.cmrojournal.com

July 2014

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no relevant financial or other relationships to disclose. Acknowledgments The authors thank Nicholas D. Smith PhD for editorial support. Previous presentation: Parts of this study were reported as an abstract and poster (abstract 998-P) at the 71st Annual Scientific Sessions of the American Diabetes Association, 24–28 June 2011, San Diego, CA, USA; and as an abstract and oral presentation (abstract 148) at the 47th Annual Meeting of the European Association for the Study of Diabetes (EASD), 12–16 September 2011, Lisbon, Portugal.

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