Efficacy and safety of luseogliflozin added to insulin therapy in Japanese patients with type 2 diabetes: a multicenter, 52-week, clinical study with a 16-week, double-blind period and a 36-week, open-label period

Abstract

Objective: To evaluate the efficacy and safety of luseogliflozin in Japanese patients with type 2 diabetes (T2D) inadequately controlled with insulin monotherapy.

Methods: This 52-week multicenter study entailed a 16-week, double-blind period followed by a 36-week, open-label period. Patients were randomized to receive either luseogliflozin 2.5 mg (n = 159) or placebo (n = 74) during the double-blind period. All patients who entered the open-label period received luseogliflozin. Major efficacy endpoints included the changes from baseline in HbA1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and bodyweight. Safety assessments included adverse events, laboratory tests and vital signs.

Results: In the double-blind period, luseogliflozin significantly decreased HbA1c (−1.18%), FPG (−42.4 mg/dL), 2 hour PPG (−68.7 mg/dL) and bodyweight (−1.27 kg) compared with placebo (all p < .001); these reductions were maintained over 52 weeks. The changes from baseline at Week 52 were −1.00%, −35.1 mg/dL, −68.8 mg/dL and −1.81 kg, respectively (all p < .001). In the placebo group, favorable glycemic control and bodyweight reduction were also observed after switching to luseogliflozin. Most adverse events were mild in severity. During the double-blind period, the incidences of hypoglycemia were 20.8% and 13.5% in the luseogliflozin and placebo groups, respectively. During the 52 weeks of luseogliflozin treatment, the frequency of hypoglycemia was 33.3%, but no serious hypoglycemia occurred. The safety profile other than hypoglycemia was also acceptable. There were no new safety concerns about luseogliflozin added to insulin.

Conclusion: Luseogliflozin added to insulin therapy significantly improved glycemic control with bodyweight reduction and was well tolerated in Japanese patients with T2D.

Clinical trial registration: Japan Pharmaceutical Information Center (JapicCTI-142582).

Keywords:

• Luseogliflozin
• sodium–glucose co-transporter 2 inhibitor
• insulin
• Japanese
• type 2 diabetes mellitus
• randomized controlled trial

Introduction

Type 2 diabetes (T2D) is a metabolic disorder characterized by chronic hyperglycemia associated with beta-cell dysfunction and insulin resistance in peripheral tissues¹. Such chronic hyperglycemia causes microvascular and macrovascular complications, resulting in deterioration of quality of life and reduction of life expectancy^2,3.

Insulin therapy lowers blood glucose and improves glycemic control as monotherapy or in combination with anti-diabetic agents. However, the risks of hypoglycemia and undesirable weight gain are elevated when the insulin dose is increased to achieve glycemic control⁴. These side effects result in not only attenuation of the treatment effect but also deterioration in medication compliance due to fear of hypoglycemia⁵.

Sodium–glucose co-transporter 2 (SGLT2) inhibitors are a novel class of oral anti-diabetic drug. SGLT2 inhibitors enhance urinary glucose excretion and reduce plasma glucose levels in an insulin-independent manner; these effects are also associated with bodyweight reduction⁶. There is limited risk of hypoglycemia when SGLT2 inhibitors are administered as monotherapy or combination therapy with other oral anti-diabetic drugs⁶. SGLT2 inhibitor + insulin therapy has been evaluated in several studies^7–9; however, data on long-term combination therapy for T2D in Japanese patients are limited¹⁰.

Luseogliflozin, an SGLT2 inhibitor approved in Japan in 2014, has shown good results in achieving glycemic control and weight reduction as monotherapy or when combined with other oral anti-diabetic drugs or glucagon-like peptide 1 (GLP-1) receptor agonists, and was found to be well tolerated with a low risk of hypoglycemia in previous clinical studies^11–16. These previous studies suggest that luseogliflozin added to insulin therapy might improve glycemic control without the increased risk of hypoglycemia and weight gain associated with insulin therapy^15,16. In the present study, we investigated the efficacy and safety of luseogliflozin added to insulin monotherapy in Japanese T2D patients with inadequate glycemic control.

Methods

Study design

This multicenter, randomized, double-blind study was conducted at 43 institutions in Japan (Supplementary Table S1) between June 2014 and March 2016. We designed this study based on Japanese guidelines¹⁷. This study was registered with the Japan Pharmaceutical Information Center (identifier: JapicCTI-142582). The study was implemented in accordance with Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki and approved by the institutional review board of each participating institution. Written informed consent was obtained from all enrolled patients.

Eligibility criteria

Japanese T2D patients were eligible if they satisfied the following criteria: stable diet therapy and prescription of insulin monotherapy at a fixed daily dose ranging from 8 to 40 units for ≥12 weeks before starting luseogliflozin; age ≥20 years; HbA1c of 7.5%–10.5%; and a maximum change in HbA1c of 1.0% during the 4-week observation period. Patients received one of the following insulin regimens: (1) premixed (the ratio of rapid/ultra-rapid insulin was 25% or 30%), (2) intermediate-acting or (3) long-acting.

Important exclusion criteria were as follows: diabetes other than T2D (e.g. type 1, gestational), other endocrine disorder likely to affect plasma glucose, use of anti-diabetic drugs other than insulin within the 8 weeks before the observation period, history of nephrectomy or renal transplantation, renal disorder requiring active treatment, estimated glomerular filtration rate of <45 mL/min/1.73 m² during the observation period, urinary tract or genital infection, obvious dysuria, obvious clinical hepatic disorder (elevation in alanine aminotransferase or aspartate aminotransferase ≥2.5 times the upper limit of normal), blood pressure >170/100 mmHg, change in antihypertensive drugs during the observation period, severe diabetic microangiopathy, and severe cardiovascular disease. Additional exclusion criteria are shown in the Supplementary Material.

Interventions

Patients were randomized (2:1) to receive luseogliflozin 2.5 mg or placebo. The study drug controller randomly allocated study drugs to the study groups and then prepared the randomization schedule. The registration center allocated the study drug to each eligible patient in a serial manner. The study drugs were provided in packs and tablets that were indistinguishable from each other during the 16-week, double-blind treatment period. To maintain blinding, urinary glucose tests by the medical institutions or patients were prohibited during the 16-week double-blind treatment period.

All participants who completed the 4-week observation period and 16-week, double-blind treatment period proceeded to the 36-week, open-label treatment period and received luseogliflozin. Thus, patients could be divided into two main treatment groups: (1) those who received luseogliflozin in the 16-week period as well as the subsequent 36-week period (LUSEO/LUSEO group) and (2) those who received placebo in the 16-week period followed by luseogliflozin in the 36-week period (PBO/LUSEO group). Luseogliflozin was orally administered at a dose of 2.5 mg once daily before breakfast. The dose of luseogliflozin could be increased to 5 mg at Weeks 28, 32, 36 or 40 if HbA1c was ≥7.4% at the corresponding visit and if there were no safety concerns (Figure 1). Other anti-diabetic drugs were prohibited from 12 weeks before starting luseogliflozin to the end of the study. Hypolipidemic, antihypertensive and diuretic drugs were permitted, provided they were prescribed at a constant dose throughout the study. Diet with or without exercise regimens at registration was continued throughout the study except when adverse events (AEs) occurred.

Figure 1. Study design. When patients provided written informed consent, those who had been administered insulin + an oral anti-diabetic drug entered the washout period. Patients treated with insulin monotherapy entered the observation period. If the prespecified criteria were met, the investigators could increase the luseogliflozin dose to 5 mg between Weeks 28 and 40.

Criteria for insulin up/down-titration

In principle, insulin type and regimen could not be changed during the treatment period. However, during the 16-week, double-blind treatment period, the insulin dose could be up-titrated if both of the following factors were satisfied: (i) fasting blood glucose level was >240 mg/dL on two consecutive visits and (ii) the investigator determined that no safety concerns would arise with an increase of the insulin dose. The insulin dose could be down-titrated if both of the following factors were satisfied: (i) there were symptoms of hypoglycemia and self-monitored blood glucose (SMBG) level on one occasion was <70 mg/dL; if no SMBG levels were available, the investigator determined that the symptoms were due to hypoglycemia; or if there were no symptoms of hypoglycemia, SMBG levels were <80 mg/dL on two or more consecutive measurements and the investigator determined that the risk of hypoglycemia was high; and (ii) the investigator determined that no safety concerns would arise with reduction of the insulin dose.

During the 36-week, open-label treatment period, up/down-titration of the insulin dose was allowed when the investigator believed that the change was therapeutically necessary to ensure safety.

Assessments

HbA1c, fasting plasma glucose (FPG), glycosylated albumin, bodyweight and vital signs (except 12-lead electrocardiogram [ECG]) were assessed at all visits. A meal tolerance test (plasma glucose, glucagon and serum C-peptide immunoreactivity) was performed at Weeks 0, 16 and 52. The procedure of the meal tolerance test is summarized in the Supplementary Material. Waist circumference and 12-lead ECG were evaluated at Weeks 0, 16, 28, 40 and 52. All clinical laboratory tests were conducted at an independent laboratory (LSI Medience Corp., Tokyo, Japan). Vital signs including 12-lead ECG, bodyweight and waist circumference were recorded at each institution.

Outcomes

The efficacy endpoints were HbA1c, plasma glucose, glucagon, serum C-peptide immunoreactivity, glycosylated albumin, bodyweight and waist circumference. Safety was assessed in terms of the nature and incidence of AEs as well as changes in clinical laboratory parameters and vital signs. AEs, including hypoglycemia, were evaluated by the participating investigators. They recorded severity, seriousness, causal relationship to the study drug and other information on their patients’ case report forms. Hypoglycemia was also evaluated with another classification proposed by the American Diabetes Association (ADA)¹⁸ based on the information about hypoglycemia in the case report recorded by the investigators.

Statistical analyses

Efficacy and safety analyses were performed on the same dataset, which comprised all patients who received the study drug at least once and underwent examination/observation after study drug administration.

The heterogeneity of patient characteristics (with a significance level of 15%, two-sided) was examined by intergroup comparisons of baseline characteristics using the χ² test or two-sample t-test.

Basic statistics and changes from baseline (Week 0) of each efficacy and safety endpoint were calculated at each evaluation point. In the PBO/LUSEO group, the changes from the end of the double-blind treatment period (EOT) were calculated during the 36-week, open-label treatment period. In the 16-week, double-blind treatment period, differences between the luseogliflozin group and placebo group in the change of efficacy endpoints at EOT were evaluated. For the evaluation of HbA1c, FPG, area under the concentration–time curve for 0–2 hours [AUC_0–2h] during the meal tolerance test for glucose level and glycosylated albumin, analysis of covariance was carried out using the value at the start of the double-blind treatment period as the covariate. For the evaluation of other efficacy endpoints, the two-sample t-test was applied. When data were missing or deemed unacceptable at EOT, the last observation carried forward method was applied. In the 52-week treatment period, mean changes from baseline for each efficacy endpoint were evaluated by one-sample t-test (missing or unacceptable data were not imputed). In both analyses, the significance level was set at 5% (two-sided) and the confidence coefficient was set at 95% (two-sided).

AEs were classified according to System Organ Class and Preferred Term defined by the Japanese version of the Medical Dictionary for Regulatory Activities (version 19.0). The frequency of AEs/adverse drug reactions was tabulated.

All statistical analyses were performed using SAS version 9.2 (SAS Inc., Cary, NC, USA). The sample size calculation is described in the Supplementary Material.

Results

Patients

Of the 334 patients who gave written informed consent, 233 were randomized to the luseogliflozin group (n = 159) or the placebo group (n = 74). Among them, 156 patients in the luseogliflozin group and 64 patients in the placebo group entered the 36-week, open-label period, and 143 patients and 56 patients completed the 52-week study, respectively (Figure 2). Both groups showed comparable demographic and baseline characteristics, including the mean daily dose of insulin. The distribution of the insulin types used was also similar in both groups (Table 1).

Figure 2. Patient disposition.

Table 1. Patient demographics and baseline characteristics.

	Placebo (n = 74)	Luseogliflozin (n = 159)	p value
Sex, n (%)			.814^a
Male	51 (68.9)	112 (70.4)
Female	23 (31.1)	47 (29.6)
Age (years)	57.1 (10.9)	57.4 (10.3)	.840^b
Bodyweight (kg)	69.13 (12.16)	68.10 (11.32)	.527^b
BMI (kg/m^2)	25.15 (3.44)	25.42 (3.53)	.585^b
Waist circumference (cm)	90.62 (8.27)	89.91 (8.73)	.559^b
Duration of diabetes (years)	12.1 (6.8)	11.7 (7.6)	.669^b
Insulin type, n (%)			.327^a
Intermediate-acting	1 (1.4)	0 (0.0)	–
Premixed	14 (18.9)	33 (20.8)	–
Long-acting	59 (79.7)	126 (79.2)	–
Daily dose of insulin (U/day)	18.1 (7.9)	17.5 (8.1)	.583^b
HbA1c (%)	8.84 (0.83)	8.70 (0.83)	.243^b
FPG (mg/dL)	172.9 (42.2)	165.7 (40.2)	.212^b
PPG (2 h)(mg/dL)	316.5 (64.7)	304.7 (65.1)	.196^b
Fasting plasma CPR (ng/mL)	1.09 (0.58)	1.03 (0.57)	.410^b
eGFR (mL/min/1.73 m^2)	87.9 (20.2)	86.5 (19.3)	.607^b

Data shown as mean (SD) unless otherwise indicated.

Abbreviations. BMI, body mass index; HbA1c, hemoglobin A1c; FPG, fasting plasma glucose; PPG, postprandial plasma glucose; CPR, C-peptide immunoreactivity; eGFR, estimated glomerular filtrate rate; SD, standard deviation.

^aChi-square test.

^bTwo-sample t-test.

Heterogeneity between the study groups was evaluated using a significance level of p < .15 (two-sided).

The proportion of patients who underwent a dose increase to 5 mg luseogliflozin in the open-label period was 62.2% in the LUSEO/LUSEO group and 59.4% in the PBO/LUSEO group. The dose of luseogliflozin for one patient was decreased to 2.5 mg after dose escalation to prevent hypoglycemia, and hypoglycemia did not develop.

Efficacy

HbA1c, FPG

In the first 16-week, double-blind period, the luseogliflozin group showed significant reductions in HbA1c and FPG compared with the placebo group. The luseogliflozin group showed sustained HbA1c reduction for 8 weeks after administration and it was maintained to the end of the double-blind period, in contrast to the placebo group, in which HbA1c increased with time. The between-group difference in HbA1c at the end of the double-blind period was −1.18% (95% confidence interval [CI], −1.39 to −0.98) (Figure 3). FPG markedly decreased in the luseogliflozin group and the significant reduction of FPG was sustained to the end of the double-blind period, in contrast to the slight increase observed in the placebo group. The between-group difference in FPG at the end of the double-blind period was −42.4 mg/dL (95% CI, −51.4 to −33.5) (Figure 4). At the end of the double-blind treatment period, the change in the daily dose of insulin in the luseogliflozin group was −0.7 ± 0.1 U/day (mean ± SE) and the change in the placebo group was 0.5 ± 0.2 U/day. The between-group difference in the daily dose of insulin was −1.2 U/day (95% CI, −1.7 to −0.7).

Figure 3. Changes in HbA1c from baseline to each visit (double-blind period). The values are shown as mean ± standard error. Differences between the luseogliflozin and placebo groups were analyzed by analysis of covariance with the baseline value as a covariate. *p < .001 versus placebo. Abbreviation. HbA1c, Hemoglobin A1c; EOT, end of double-blind treatment period.

Figure 4. Changes in FPG from baseline to each visit (double-blind period). The values are shown as mean ± standard error. Differences between the luseogliflozin and placebo groups were analyzed by analysis of covariance with the baseline value as a covariate. *p < .001 versus placebo. Abbreviations. FPG, fasting plasma glucose; EOT, end of double-blind treatment period.

During the 52-week treatment period, the significant reductions of HbA1c and FPG from baseline (Week 0) were maintained to Week 52 in the LUSEO/LUSEO group (Figures 5 and 6). The mean changes from baseline in HbA1c and FPG at Week 52 were −1.00% (95% CI, −1.14 to −0.86) and −35.1 mg/dL (95% CI, −41.2 to −29.1), respectively. In the PBO/LUSEO group, HbA1c and FPG markedly decreased after luseogliflozin administration and the significant reductions from EOT were sustained to Week 52. The mean changes from EOT in HbA1c and FPG at Week 52 were −1.28% (95% CI, −1.48 to −1.08) and −39.0 mg/dL (95% CI, −48.6 to −29.3), respectively. The change in daily dose of insulin from baseline to Week 52 was −0.8 ± 0.2 U/day (95% CI, −1.3 to −0.4) in the LUSEO/LUSEO group.

Figure 5. Time-course of HbA1c over 52 weeks. The values are shown as mean ± standard error. *p < .05 versus baseline (one-sample t-test). **p < .001 versus baseline (one-sample t-test). Abbreviations. HbA1c, hemoglobin A1c; LUSEO/LUSEO, patients who received luseogliflozin during both double-blind and open-label periods; PBO/LUSEO, patients who received placebo during the double-blind period and luseogliflozin during the open-label period.

Figure 6. Changes in FPG from baseline to each visit over 52 weeks. The values are shown as mean ± standard error. In the PBO/LUSEO group, from Week 20 to Week 52, the change from at the end of double-blind treatment period was calculated. **p < .001 versus baseline (one-sample t-test). Abbreviation. FPG, fasting plasma glucose; LUSEO/LUSEO, patients who received luseogliflozin during both double-blind and open-label periods; PBO/LUSEO, patients who received placebo during the double-blind period and luseogliflozin during the open-label period.

Meal tolerance test

In the 16-week, double-blind period, postprandial plasma glucose (PPG) in the luseogliflozin group was significantly decreased compared with baseline (Week 0) at all evaluation points (0.5, 1 and 2 hours after meal), while PPG in the placebo group changed little compared with baseline (Figure 7). The change in PPG 2 hours after the meal was −73.6 mg/dL (95% CI, −82.0 to −65.3) in the luseogliflozin group and −5.0 mg/dL (95% CI, −17.5 to 7.6) in the placebo group. The between-group difference in PPG (2 h) at EOT was −68.7 mg/dL (95% CI, −83.7 to −53.7).

Figure 7. Changes in plasma glucose during meal tolerance test at Weeks 0 and EOT (double-blind period). The values are shown as mean ± standard error. At 0 hrs, differences between the luseogliflozin and placebo groups were analyzed by analysis of covariance with the baseline value as a covariate. *p < .001 versus placebo. At other time points, a two-sample t-test was used to analyze the difference between the luseogliflozin and placebo groups. **p < .001 versus placebo (two-sample t-test). Abbreviations. FPG, fasting plasma glucose; EOT, end of double-blind treatment period.

During the 52-week treatment period, the significant reductions of PPG from baseline at Week 16 were maintained until Week 52 in the LUSEO/LUSEO group. The mean change in PPG (2 h) from baseline to Week 52 was −68.8 mg/dL (95% CI, −77.9 to −59.6). After commencement of luseogliflozin, a significant reduction of PPG was seen at Week 52 in the PBO/LUSEO group, similar to the LUSEO/LUSEO group. The mean change in PPG (2 h) from EOT to Week 52 was −65.5 mg/dL (95% CI, −79.8 to −51.2) (Figure 8).

Figure 8. Changes in plasma glucose during the meal tolerance test at Weeks 0, 16 and 52. The values are shown as mean ± standard error. *p < .001 versus baseline at Week 16 and **p < .001 versus baseline at Week 52 (one-sample t-test). Abbreviation. LUSEO/LUSEO, patients who received luseogliflozin during both double-blind and open-label periods; PBO/LUSEO, patients who received placebo during the double-blind period and luseogliflozin during the open-label period.

Regarding other parameters, fasting serum C-peptide immunoreactivity in the luseogliflozin group was significantly decreased compared with the placebo group at the end of the double-blind period (Table 2). During the 52-week treatment period, significant reduction of fasting serum C-peptide immunoreactivity at Week 52 from baseline was seen in the LUSEO/LUSEO group (Table 3). There were no statistically significant differences in fasting glucagon between the luseogliflozin group and placebo group in the double-blind period (Table 2). At Week 52, a statistically significant increase from baseline in fasting glucagon was observed in both the LUSEO/LUSEO and PBO/LUSEO groups (Table 3).

Table 2. Change in efficacy variables from baseline to end of the double-blind treatment period.

	Placebo		Luseogliflozin 2.5 mg		Difference compared with placebo
	n	Mean (SD)	n	Mean (SD)
HbA1c (%)
Baseline	74	8.84 (0.83)	159	8.70 (0.83)	–
EOT	74	9.23 (1.16)	159	7.96 (0.77)	–
Change from BL	0.39 (0.22, 0.56)		−0.74 (−0.87, −0.62)		−1.18 (−1.39, −0.98)^a
FPG (mg/dL)
Baseline	74	172.9 (42.2)	159	165.7 (40.2)	–
EOT	74	178.4 (46.5)	159	132.8 (31.3)	–
Change from BL	5.5 (−2.9, 13.9)		−33.0 (−39.3, −26.6)		−42.4 (−51.4, −33.5)^a
PPG (2 h) (mg/dL)
Baseline	74	316.5 (64.7)	159	304.7 (65.1)	–
EOT	69	308.1 (59.9)	155	230.7 (49.1)	–
Change from BL	−5.0 (−17.5, 7.6)		−73.6 (−82.0, −65.3)		−68.7 (−83.7, −53.7)^a
PPG (AUC0–2h) (mg h/dL)
Baseline	74	559 (104)	159	547 (98.2)	–
EOT	69	561 (93.4)	155	438 (67.7)	–
Change from BL	3.66 (−15.7, 23.1)		−109 (−122, −95.4)		−118 (−135, −99.9)^a
Glycosylated albumin (%)
Baseline	74	25.07 (3.80)	159	24.20 (3.40)	–
EOT	74	26.00 (4.14)	159	20.54 (2.95)	–
Change from BL	0.93 (0.37, 1.50)		−3.66 (−4.12, −3.21)		−4.90 (−5.59, −4.21)^a
Bodyweight (kg)
Baseline	74	69.13 (12.16)	159	68.10 (11.32)	–
EOT	74	69.08 (12.19)	159	66.78 (11.54)	–
Change from BL	−0.05 (−0.39, 0.28)		−1.32 (−1.57, −1.07)		−1.27 (−1.69, −0.84)^a
Waist circumference (cm)
Baseline	74	90.62 (8.27)	159	89.91 (8.73)	–
EOT	73	90.76 (8.00)	158	88.79 (8.74)	–
Change from BL	0.04 (−0.64, 0.71)		−1.16 (−1.62, -0.71)		−1.20 (−2.01, −0.39)^b
Fasting serum CPR (ng/mL)
Baseline	74	1.09 (0.58)	159	1.03 (0.57)	–
EOT	73	1.19 (0.68)	158	0.98 (0.63)	–
Change from BL	0.08 (−0.03, 0.19)		−0.05 (−0.11, 0.01)		−0.13 (−0.25, −0.01)^b
Fasting glucagon (pg/mL)
Baseline	74	87.0 (25.4)	158	86.3 (26.2)	–
EOT	69	91.4 (22.7)	154	92.0 (26.9)	–
Change from BL	4.5 (−0.3, 9.3)		5.9 (2.4, 9.4)		1.5 (−4.6, 7.6)

Changes from BL and difference compared with placebo are shown with 95% confidence intervals.

Abbreviations. BL, baseline; EOT, end of double-blind treatment period; HbA1c, hemoglobin A1c; FPG, fasting plasma glucose; PPG, postprandial plasma glucose; AUC_0–2h, area under the concentration-time curve for 0–2 h during the meal tolerance test; CPR, C-peptide immunoreactivity; SD, standard deviation.

^ap < .001 versus placebo.

^bp < .05 versus placebo.

Table 3. Efficacy variables.

	PBO/LUSEO group			LUSEO/LUSEO group
	n	Mean (SD)	Change from BL (95% CI)	n	Mean (SD)	Change from BL (95% CI)
HbA1c (%)
Week 0	74	8.84 (0.83)	–	159	8.70 (0.83)	–
Week 16	65	9.02 (0.98)	0.29 (0.12, 0.46)^a	156	7.94 (0.75)	−0.77 (−0.89, −0.65)^a
Week 28	62	7.88 (0.76)	−1.13 (−1.27, −1.00)^a	154	7.72 (0.79)	−0.99 (−1.13, −0.85)^a
Week 52	56	7.65 (0.63)	−1.28 (−1.48, −1.08)^a	143	7.69 (0.77)	−1.00 (−1.14, −0.86)^a
FPG (mg/dL)
Week 0	74	172.9 (42.2)	–	159	165.7 (40.2)	–
Week 16	65	172.7 (43.4)	3.4 (−5.2, 11.9)	156	130.9 (25.2)	−35.1 (−40.7, −29.5)^a
Week 28	62	133.7 (27.9)	−39.0 (−47.5, −30.5)^a	154	129.0 (28.7)	−36.8 (−42.7, −30.9)^a
Week 52	56	134.3 (26.4)	−39.0 (−48.6, −29.3)^a	143	131.5 (27.6)	−35.1 (−41.2, −29.1)^a
PPG (2 h) (mg/dL)
Week 0	74	316.5 (64.7)	–	159	304.7 (65.1)	–
Week 16	65	303.6 (57.0)	−4.3 (−17.3, 8.6)	156	231.1 (49.2)	−74.0 (−82.3, −65.6)^a
Week 52	56	234.3 (46.6)	−65.5 (−79.8, −51.2)^a	142	234.0 (49.3)	−68.8 (−77.9, −59.6)^a
PPG (AUC0–2h) (mg h/dL)
Week 0	74	559 (104)	–	159	547 (98.2)	–
Week 16	65	553 (93.0)	5.43 (−14.8, 25.7)	156	439 (67.8)	−109 (−122, −95.7)^a
Week 52	56	445 (62.6)	−107 (−129, −84.5)^a	142	442 (67.9)	−104 (−119, −89.7)^a
Glycosylated albumin (%)
Week 0	74	25.07 (3.80)	–	159	24.20 (3.40)	–
Week 16	65	25.42 (3.77)	0.56 (0.00, 1.12)	156	20.51 (2.92)	−3.77 (−4.20, −3.34)^a
Week 28	62	21.06 (3.20)	−4.38 (−4.93, −3.83)^a	154	20.53 (3.04)	−3.78 (−4.25, −3.30)^a
Week 52	56	20.17 (2.95)	−4.72 (−5.46, −3.98)^a	143	20.10 (2.83)	−4.05 (−4.54, −3.56)^a
Bodyweight (kg)
Week 0	74	69.13 (12.16)	–	159	68.10 (11.32)	–
Week 16	65	68.73 (12.28)	0.00 (−0.36, 0.36)	156	66.76 (11.63)	−1.30 (−1.54, −1.05)^a
Week 28	62	67.00 (12.21)	−1.44 (−1.75, −1.12)^a	154	66.30 (11.59)	−1.68 (−1.99, −1.38)^a
Week 52	56	67.72 (12.45)	−1.52 (−2.05, −0.98)^a	143	66.62 (11.35)	−1.81 (−2.19, −1.43)^a
Waist circumference (cm)
Week 0	74	90.62 (8.27)	–	159	89.91 (8.73)	–
Week 16	65	90.15 (8.13)	−0.11 (−0.82, 0.60)	156	88.63 (8.76)	−1.18 (−1.64, −0.72)^a
Week 28	61	88.76 (8.33)	−1.13 (−1.76, −0.49)^b	153	88.35 (9.12)	−1.32 (−1.78, −0.85)^a
Week 52	56	89.11 (8.65)	−1.32 (−2.11, −0.54)^b	143	88.19 (8.99)	−1.73 (−2.36, −1.11)^a
Fasting serum CPR (ng/mL)
Week 0	74	1.09 (0.58)	–	159	1.03 (0.57)	–
Week 16	65	1.17 (0.70)	0.07 (−0.05, 0.18)	156	0.97 (0.63)	−0.06 (−0.12, 0.01)
Week 28	62	0.98 (0.72)	−0.20 (−0.33, −0.07)^b	154	0.93 (0.60)	−0.10 (−0.17, −0.04)^b
Week 52	56	1.04 (1.04)	−0.18 (−0.40, 0.04)	143	0.94 (0.54)	−0.12 (−0.18, −0.05)^a
Fasting glucagon (pg/mL)
Week 0	74	87.0 (25.4)	–	158	86.3 (26.2)	–
Week 16	65	91.2 (23.0)	4.8 (−0.3, 9.9)	155	92.0 (26.8)	5.8 (2.3, 9.3)^b
Week 52	56	99.4 (27.9)	7.3 (1.9, 12.7)^b	142	101.3 (26.9)	15.1 (11.9, 18.3)^a

The LUSEO/LUSEO group includes patients who were administered luseogliflozin throughout the entire 52 weeks. The PBO/LUSEO group includes patients who received luseogliflozin only in the open-label period (those who received luseogliflozin for 36 weeks). In the PBO/LUSEO group at Weeks 28 and 52 (during the 36-week, open-label period), the changes were measured from the end of the double-blind treatment period.

Abbreviations. BL, baseline; CI, confidence interval; HbA1c, hemoglobin A1c; FPG, fasting plasma glucose; PPG, postprandial plasma glucose; AUC_0–2h, area under the concentration–time curve for 0–2 h during the meal tolerance test; CPR, C-peptide immunoreactivity; SD, standard deviation.

^ap < .001 versus baseline.

^bp < .05 versus baseline.

Bodyweight

In the 16-week, double-blind period, the luseogliflozin group showed a significant reduction in bodyweight compared with the placebo group. The decrease in bodyweight persisted in the luseogliflozin group; in contrast, bodyweight did not appreciably change in the placebo group. The between-group difference in bodyweight at EOT was −1.27 kg (95% CI, −1.69 to −0.84) (Figure 9).

Figure 9. Changes in bodyweight from baseline to each visit (double-blind period). The values are shown as mean ± standard error. *p < .001 versus placebo (two-sample t-test). Abbreviation. EOT, end of double-blind treatment period.

During the 52-week treatment period, bodyweight decreased steadily from baseline in the LUSEO/LUSEO group; this change was maintained up to Week 52 (Figure 10). The mean change from baseline in bodyweight at Week 52 was −1.81 kg (95% CI, −2.19 to −1.43). In the PBO/LUSEO group, bodyweight declined after luseogliflozin commencement; the reduction in bodyweight remained to Week 52. The mean change from EOT in bodyweight was −1.52 kg (95% CI, −2.05 to −0.98). Furthermore, we also observed a significant decrease in waist circumference in the luseogliflozin group compared with the placebo group. The between-group difference in waist circumference at EOT was −1.20 cm (95% CI, −2.01 to −0.39). The mean change in waist circumference from baseline to Week 52 was −1.73 cm (95% CI, −2.36 to −1.11) in the LUSEO/LUSEO group, and from EOT to Week 52, −1.32 cm (95% CI, −2.11 to −0.54) in the PBO/LUSEO group.

Figure 10. Changes in bodyweight from baseline to each visit over 52 weeks. The values are shown as mean ± standard error. In the PBO/LUSEO group from Week 20 to Week 52, the change from the end of the double-blind period was calculated. **p < .001 versus baseline (one-sample t-test). Abbreviations. LUSEO/LUSEO, patients who received luseogliflozin during both double-blind and open-label periods; PBO/LUSEO, patients who received placebo during the double-blind period and luseogliflozin during the open-label period.

Other efficacy variables are shown in Tables 2 and 3.

Safety

During the 16-week, double-blind period

Patients treated with luseogliflozin had a similar incidence of AEs and adverse drug reactions (51.6% and 26.4%, respectively) compared with the placebo group (56.8% and 16.2%, respectively). No deaths were reported in either treatment group. The incidence of serious AEs (SAEs) and AEs leading to discontinuation was higher in the placebo group (2.7% and 5.4%, respectively) than in the luseogliflozin group (0.6% and 0.6%, respectively) (Table 4). The most frequent AE was hypoglycemia (20.8%) in the luseogliflozin group and nasopharyngitis (27.0%) in the placebo group. Most AEs were mild in severity.

Table 4. Summary of adverse events.

	16-week double-blind period				Entire 52-week study
	Placebo		Luseogliflozin		PBO/LUSEO group (36 weeks)		LUSEO/LUSEO group (52 weeks)
	n = 74		n = 159		n = 64		n = 159
Any AE	42	(56.8)	82	(51.6)	37	(57.8)	128	(80.5)
Any ADR	12	(16.2)	42	(26.4)	21	(32.8)	75	(47.2)
Any SAE	2	(2.7)	1	(0.6)	3	(4.7)	8	(5.0)
AEs leading to discontinuation	4	(5.4)	1	(0.6)	4	(6.3)	8	(5.0)
AEs of special interest
Hypoglycemia	10	(13.5)	33	(20.8)	14	(21.9)	53	(33.3)
Hypoglycemia	9	(12.2)	33	(20.8)	14	(21.9)	53	(33.3)
Hypoglycemia unawareness	1	(1.4)	0	(0.0)	0	(0.0)	0	(0.0)
Urinary tract infections	0	(0.0)	4	(2.5)	0	(0.0)	8	(5.0)
Cystitis	0	(0.0)	2	(1.3)	0	(0.0)	4	(2.5)
Urinary tract infection	0	(0.0)	2	(1.3)	0	(0.0)	4	(2.5)
Genital infections	0	(0.0)	4	(2.5)	1	(1.6)	4	(2.5)
Genital herpes	0	(0.0)	1	(0.6)	0	(0.0)	1	(0.6)
Vulvovaginal candidiasis	0	(0.0)	4	(2.5)	1	(1.6)	4	(2.5)
AEs related to pollakiuria	2	(2.7)	14	(8.8)	6	(9.4)	16	(10.1)
Pollakiuria	1	(1.4)	14	(8.8)	5	(7.8)	16	(10.1)
Polyuria	1	(1.4)	0	(0.0)	0	(0.0)	0	(0.0)
Nocturia	0	(0.0)	0	(0.0)	1	(1.6)	0	(0.0)
AEs related to volume depletion	1	(1.4)	7	(4.4)	4	(6.3)	9	(5.7)
Thirst	1	(1.4)	6	(3.8)	3	(4.7)	7	(4.4)
Dehydration	0	(0.0)	1	(0.6)	1	(1.6)	2	(1.3)
Skin disorders	3	(4.1)	4	(2.5)	1	(1.6)	10	(6.3)
Eczema	0	(0.0)	1	(0.6)	1	(1.6)	1	(0.6)
Eczema nummular	1	(1.4)	0	(0.0)	0	(0.0)	0	(0.0)
Rash	2	(2.7)	1	(0.6)	0	(0.0)	4	(2.5)
Urticaria	0	(0.0)	2	(1.3)	0	(0.0)	2	(1.3)
Dermatitis contact	0	(0.0)	0	(0.0)	0	(0.0)	2	(1.3)
Rash generalized	0	(0.0)	0	(0.0)	0	(0.0)	1	(0.6)

Data shown as n (%).

The LUSEO/LUSEO group includes patients who were administered luseogliflozin throughout the entire 52 weeks. The PBO/LUSEO group includes patients who received luseogliflozin only in the open-label period (those who received luseogliflozin for 36 weeks).

Abbreviations. AE, adverse event; ADR, adverse drug reaction; SAE, serious adverse event.

AEs of special interest related to SGLT2 inhibitors (except skin disorders) were more frequent in the luseogliflozin group than the placebo group. The incidence of hypoglycemia was 20.8% in the luseogliflozin group and 13.5% in the placebo group. Hypoglycemia (casual blood glucose <40 mg/dL) leading to discontinuation from the study was observed only in the placebo group (Figure 2). All hypoglycemia events in both groups were judged to be mild in severity by the investigators and patients recovered spontaneously or with meal intake. Based on the classification of hypoglycemia proposed by the ADA¹⁸, there were no episodes of “severe hypoglycemia” in either group that required the assistance of another person. Although the frequency of “documented symptomatic hypoglycemia” (presence of symptoms and blood glucose level ≤70 mg/dL) in the luseogliflozin group was higher than that in the placebo group, there were no notable differences between the luseogliflozin and placebo groups for other classifications (Table 5). The frequency of hypoglycemia was not strongly affected by the type of insulin used.

Table 5. Details of hypoglycemia.

	16-week double-blind period				Entire 52-week study
	Placebo		Luseogliflozin		PBO/LUSEO group (36 weeks)		LUSEO/LUSEO group (52 weeks)
	n = 74		n = 159		n = 64		n = 159
Hypoglycemia	10	(13.5)	33	(20.8)	14	(21.9)	53	(33.3)
Drug-related hypoglycemia	8	(10.8)	30	(18.9)	12	(18.8)	47	(29.6)
Severity judged by the investigators
Severe	0	(0.0)	0	(0.0)	0	(0.0)	0	(0.0)
Moderate	0	(0.0)	0	(0.0)	0	(0.0)	1	(0.6)
Mild	10	(13.5)	33	(20.8)	14	(21.9)	52	(32.7)
Re-categorized by ADA guidelines^a
Severe hypoglycemia	0	(0.0)	0	(0.0)	0	(0.0)	0	(0.0)
Documented symptomatic hypoglycemia	1	(1.4)	12	(7.5)	5	(7.8)	18	(11.3)
Asymptomatic hypoglycemia	4	(5.4)	11	(6.9)	4	(6.3)	15	(9.4)
Probable symptomatic hypoglycemia	4	(5.4)	5	(3.1)	3	(4.7)	7	(4.4)
Relative hypoglycemia	1	(1.4)	5	(3.1)	2	(3.1)	10	(6.3)
Type of insulin
Premixed or intermediate-acting
n	15	(20.3)	33	(20.8)	12	(18.8)	33	(20.8)
Daily dose of insulin (U)	26.3	(8.1)	21.3	(7.5)	26.3	(7.8)	21.3	(7.5)
Hypoglycemia	3	(20.0)	10	(30.3)	3	(25.0)	14	(42.4)
Long-acting
n	59	(79.7)	126	(79.2)	52	(81.3)	126	(79.2)
Daily dose of insulin (U)	16.1	(6.4)	16.5	(8.0)	15.9	(6.4)	16.5	(8.0)
Hypoglycemia	7	(11.9)	23	(18.3)	11	(21.2)	39	(31.0)

Data shown as n (%) or mean (SD).

The LUSEO/LUSEO group includes patients who were administered luseogliflozin throughout the entire 52 weeks. The PBO/LUSEO group includes patients who received luseogliflozin only in the open-label period (those who received luseogliflozin for 36 weeks).

^aIn the LUSEO/LUSEO group, three patients who were unclassifiable in any category by ADA guideline were not included.

Abbreviation. ADA, American Diabetes Association.

Regarding laboratory test results, hematocrit, blood urea nitrogen, fasting acetoacetic acid and fasting β-hydroxybutyric acid in the luseogliflozin group were increased compared with the placebo group. Systolic blood pressure, diastolic blood pressure and pulse in the luseogliflozin group were significantly decreased compared with the placebo group at EOT. No clinically abnormal 12-lead ECG findings were observed. The changes in safety-related variables are shown in Table 6.

Table 6. Change in safety variables from baseline to end of the double-blind treatment period.

	Placebo		Luseogliflozin 2.5 mg		Difference compared with placebo
	n	Mean (SD)	n	Mean (SD)
Hematocrit (%)
Baseline	74	43.66 (3.55)	159	42.98 (3.75)	–
EOT	74	44.02 (3.87)	158	44.64 (3.94)	–
Change from BL	0.36 (−0.12, 0.85)		1.67 (1.29, 2.04)		1.30 (0.67, 1.94)^a
BUN (mg/dL)
Baseline	74	14.3 (3.3)	159	14.2 (3.7)	–
EOT	74	13.7 (3.4)	158	16.3 (4.3)	–
Change from BL	−0.6 (−1.3, 0.1)		2.1 (1.5, 2.7)		2.7 (1.6, 3.7)^a
LDL-C (mg/dL)
Baseline	74	119.5 (26.0)	159	122.6 (28.5)	–
EOT	74	120.9 (32.8)	158	126.1 (33.5)	–
Change from BL	1.5 (−3.3, 6.2)		3.8 (0.4, 7.1)		2.3 (−3.6, 8.2)
HDL-C (mg/dL)
Baseline	74	55.7 (15.6)	159	56.5 (15.5)	–
EOT	74	56.3 (15.1)	158	60.8 (15.6)	–
Change from BL	0.6 (−1.1, 2.2)		4.3 (3.2, 5.4)		3.7 (1.8, 5.7)^a
Total cholesterol (mg/dL)
Baseline	74	196.4 (33.1)	159	198.3 (34.6)	–
EOT	74	198.1 (36.9)	158	206.2 (40.7)	–
Change from BL	1.6 (−3.8, 7.1)		8.1 (4.2, 12.1)		6.5 (−0.3, 13.3)
Triglycerides (mg/dL)
Baseline	74	144.2 (115.0)	159	133.0 (111.7)	–
EOT	74	144.7 (130.5)	158	125.0 (135.0)	–
Change from BL	0.5 (−18.0, 19.0)		−7.9 (−24.4, 8.6)		−8.4 (−35.5, 18.7)
Adiponectin (µg/mL)
Baseline	74	6.78 (3.22)	159	7.17 (3.44)	–
EOT	72	6.88 (3.15)	156	7.75 (3.51)	–
Change from BL	0.11 (−0.14, 0.37)		0.57 (0.39, 0.76)		0.46 (0.14, 0.78)^b
Acetoacetic acid (fasting) (µmol/L)
Baseline	74	42.1 (40.2)	159	36.8 (30.9)	–
EOT	74	42.5 (37.9)	158	61.3 (66.5)	–
Change from BL	0.4 (−8.5, 9.2)		24.4 (15.2, 33.6)		24.0 (9.3, 38.7)^b
β-hydroxybutanoic acid (fasting) (µmol/L)
Baseline	74	95.1 (116.3)	159	85.3 (94.6)	–
EOT	74	103.8 (120.7)	158	157.7 (202.1)	–
Change from BL	8.7 (−17.9, 35.3)		72.2 (44.7, 99.6)		63.5 (19.5, 107.4)^b
Free fatty acids (mEq/L)
Baseline	74	0.525 (0.213)	159	0.514 (0.217)	–
EOT	74	0.517 (0.234)	158	0.537 (0.258)	–
Change from BL	−0.008 (−0.064, 0.047)		0.026 (−0.009, 0.062)		0.034 (−0.030, 0.098)
SBP (mmHg)
Baseline	74	129.2 (14.5)	159	127.7 (15.2)	–
EOT	74	130.4 (11.5)	158	124.7 (15.1)	–
Change from BL	1.2 (−1.5, 3.8)		−2.9 (−5.0, −0.8)		−4.1 (−7.6, −0.5)^b
DBP (mmHg)
Baseline	74	77.2 (9.2)	159	75.4 (10.1)	–
EOT	74	77.4 (9.8)	158	73.0 (10.4)	–
Change from BL	0.2 (−1.7, 2.2)		−2.3 (−3.6, −1.0)		−2.6 (−4.9, −0.3)^b
Pulse (beats/min)
Baseline	74	74.5 (12.0)	159	75.4 (11.1)	–
EOT	74	76.7 (11.8)	158	73.2 (11.7)	–
Change from BL	2.2 (0.4, 4.0)		−2.3 (−3.7, −1.0)		−4.5 (−6.9, −2.2)^a

Change from BL and difference compared with placebo are shown with 95% confidence intervals.

Abbreviations. BL, baseline; EOT, end of double-blind treatment period; BUN, blood urea nitrogen; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; SBP, systolic blood pressure; DBP, diastolic blood pressure; SD, standard deviation.

^ap < .001 versus placebo.

^bp < .05 versus placebo.

During the 52-week treatment period

The summary of AEs is shown in Table 4. No deaths were reported and most AEs were mild in severity. The frequency of SAEs and AEs leading to discontinuation was similar between the LUSEO/LUSEO group (52 weeks of treatment) and the PBO/LUSEO group (36 weeks of treatment). The most common AE was hypoglycemia in both the LUSEO/LUSEO group and PBO/LUSEO group (33.3% and 21.9%, respectively).

Regarding AEs of special interest related to SGLT2 inhibitors, in both the LUSEO/LUSEO group and the PBO/LUSEO group, common AEs (≥5% of patients) were hypoglycemia and pollakiuria, which were similar to those occurring in the 16-week, double-blind treatment period in the luseogliflozin group. There were no AEs in which frequency was greatly increased because of long-term administration of luseogliflozin (Table 4). There were no episodes of severe hypoglycemia either judged by the investigator or based on the classification of the ADA (Table 5). All patients recovered from hypoglycemia events either spontaneously or with food intake. After Week 28 (the time point when up-titration of luseogliflozin was allowed), the incidence of hypoglycemia by the patient-years method was 0.79 events/patient-year in patients who underwent a dose escalation of luseogliflozin and 0.86 events/patient-year in patients whose luseogliflozin dose was not increased in the LUSEO/LUSEO group. In the PBO/LUSEO + LUSEO/LUSEO groups, the incidence of hypoglycemia by patient-years was 0.69 events/patient-year with luseogliflozin dose escalation and 0.98 events/patient-year without luseogliflozin dose escalation.

In both the LUSEO/LUSEO and PBO/LUSEO groups, the trends in laboratory test results and vital signs were similar to those in previous luseogliflozin studies^11–14. Therefore, there were no new safety concerns in the 52-week treatment period. The changes in safety-related variables are shown in Table S2.

Discussion

The present study demonstrated that luseogliflozin added to insulin monotherapy significantly improved glycemic control along with bodyweight reduction in Japanese T2D patients. In the 16-week, double-blind period, the luseogliflozin group had significantly reduced HbA1c and fasting and postprandial glucose levels compared with the placebo group. In addition, these significant reductions from baseline were maintained during the 52-week treatment period in the LUSEO/LUSEO group. In the PBO/LUSEO group, HbA1c and FPG tended to increase during the 16-week, double-blind period; these parameters decreased markedly after luseogliflozin administration and this effect was sustained until Week 52. The significant reduction of PPG was also observed at Week 52. The percentage of patients who were up-titrated to 5 mg of luseogliflozin was comparable between the two groups. Adding luseogliflozin to insulin resulted in rapid and sustainable glycemic control in this study, consistent with previous combination studies of luseogliflozin^12,14. Therefore, the combination of luseogliflozin and insulin therapy might be a treatment option for T2D patients for whom insulin therapy does not adequately control the disease.

One of the undesirable effects associated with insulin therapy is weight gain. Weight gain might worsen insulin resistance and require an increase of insulin dose. Thus, weight control is also important to the management of T2D patients. In the 16-week, double-blind period, bodyweight of the luseogliflozin group was significantly reduced compared with the placebo group. This weight loss effect lasted to Week 52 in the LUSEO/LUSEO group, similar to previous results with luseogliflozin monotherapy and combination therapy with other oral anti-diabetic agents and GLP-1 receptor agonist^12,14. In the PBO/LUSEO group, bodyweight did not change during the 16-week placebo treatment period but a reduction was observed after luseogliflozin administration. These findings suggest that luseogliflozin added to insulin decreases bodyweight and indicate that luseogliflozin might prevent the weight gain caused by insulin treatment. Thus, luseogliflozin might be a favorable treatment option for patients who are unable to attain glycemic control on insulin therapy, and the effect on bodyweight might be an added benefit to this combination therapy.

The major safety concern of insulin therapy is hypoglycemia. In this study, the overall rate of hypoglycemia was higher than the rate noted in previous luseogliflozin monotherapy or combination studies^11–16. The higher rate of hypoglycemia in our study was likely a result of a difference in the patient population: the patients in this study were on insulin therapy, which increases the risk of hypoglycemia. The rate of hypoglycemia was also high in the placebo group during the double-blind period. However, the incidence of hypoglycemia was similar to that found in other studies of SGLT2 inhibitors plus insulin in Japanese T2D patients^10,19–22. These findings suggest that the high rate of hypoglycemia observed in this study was not a specific response to luseogliflozin. Hypoglycemia leading to discontinuation was observed only in the placebo group during the double-blind period. No severe hypoglycemia was observed and all cases of hypoglycemia recovered spontaneously or with food intake. The severity of hypoglycemia did not worsen with the extension of luseogliflozin administration during this 52-week study. Furthermore, neither the up-titration to 5 mg luseogliflozin nor the type of insulin affected the frequency of hypoglycemia. These results suggest that the hypoglycemia component of the safety profile of luseogliflozin added to insulin was generally acceptable.

Although the daily insulin dose was (in principle) fixed to accurately evaluate the efficacy and safety of luseogliflozin added to insulin therapy, a slight decrease of the daily insulin dose was observed in this study. In actual clinical settings, flexible adjustment of the insulin dose is performed depending on the patient’s conditions (glycemic control and hypoglycemia). Further investigations in clinical settings are required to evaluate the risk of hypoglycemia and the insulin-saving effect with co-administration of luseogliflozin and insulin.

Regarding the safety profile of luseogliflozin (other than hypoglycemia), most AEs were mild in severity. During the 16-week, double-blind period, the frequency of AEs was similar in both the luseogliflozin and placebo groups. SAEs and AEs leading to discontinuation in the placebo group were more frequent than those in the luseogliflozin group. Although most AEs of special interest were more frequent in the luseogliflozin group than in the placebo group, the events were consistent with those in previous luseogliflozin studies^11–16. Over the entire 52-week period, safety profiles, including ketoacidosis and overproduction of blood ketone bodies^23–25, were also consistent with those of previous luseogliflozin studies^12,14. Based on the abovementioned findings, no new safety concerns regarding long-term administration of luseogliflozin in combination with insulin therapy were found.

This study had some limitations. First, the insulin regimen and the range of the daily dose of insulin were fixed as inclusion criteria. Further investigation is necessary to evaluate this combination therapy in a real-world clinical setting. Second, the study design consisted of a 16-week, double-blind period and a 36-week, open-label period with no control group. Thus, investigator bias in safety evaluation cannot be excluded throughout the 52-week treatment period.

Conclusion

Luseogliflozin added to insulin therapy significantly improved glycemic control and led to a reduction in bodyweight; combined therapy was well tolerated. Thus, this combination therapy might be an attractive treatment option for Japanese T2D patients.

Transparency

Declaration of funding

This study was supported by Taisho Pharmaceutical Co. Ltd. The authors retained full control of the manuscript content.

Declaration of financial/other relationships

Y.S. has disclosed that he has received consulting and/or speaker’s fees from Eli Lilly Japan KK, Sanofi KK, Novo Nordisk Pharma Inc., Glaxo-Smith-Kline, Taisho Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., Astellas Pharma Inc. BD, Nippon Boehringer Ingelheim Co. Ltd., Johnson & Johnson and Takeda Pharmaceutical Company Limited; he also received clinical commissioned/joint research grants from Nippon Boehringer Ingelheim Co. Ltd., Eli Lilly and Company, Taisho Toyama Pharmaceutical Co. Ltd., MSD KK, Ono Pharmaceutical Co. Ltd., Novo Nordisk Pharma Ltd. and ARKRAY Co. Ltd. T.S. has disclosed that he has received grant/research fees from Taisho Toyama Pharmaceutical Co. Ltd. and consulting and/or speaker’s fees from Taisho Pharmaceutical Co. Ltd., Novo Nordisk Pharma Ltd., Sanofi KK and Taisho Toyama Pharmaceutical Co. Ltd. A.F. has disclosed that he has received consultant/advisor fees from Taisho Pharmaceutical Co. Ltd. H.I., H.O. and S.S. have disclosed that they are employees of Taisho Pharmaceutical Co. Ltd., which is developing luseogliflozin.

A CMRO peer reviewer on this manuscript declares consultancy work for competitors Astra Zeneca and Sanofi. Other 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.

Acknowledgements

The authors express their gratitude to the individuals who participated in the study, and are grateful to all the investigators for conducting the study. The authors thank Hironori Yamasaki and Shi Chen (Taisho Pharmaceutical Co. Ltd., Tokyo, Japan) for assistance with the statistical analysis. This study was sponsored by Taisho Pharmaceutical Co. Ltd., Tokyo, Japan. Editorial assistance was provided by William Ng, MD (Edanz Medical Writing), and was sponsored by Taisho Pharmaceutical.

Previous presentation: Part of this study was reported as an abstract and poster (abstract P-0393) at the International Diabetes Federation 2017 World Diabetes Congress, Abu Dhabi, United Arab Emirates, 4–8 December 2017.