Introduction

As lifestyle and dietary practices are fundamental contributors to the obesity and type 2 diabetes epidemics worldwide [1, 2], lifestyle changes and exercise are key aspects of treatment. However, achieving adequate glycemic control solely through lifestyle changes is difficult in many cases; thus, single- or multiple-drug therapies are indicated for the treatment of type 2 diabetes mellitus (T2DM).

Currently available oral glucose-lowering agents include sulfonylureas (SUs), biguanides, thiazolidinediones, and α-glucosidase inhibitors [3]. However, it has been reported that despite receiving these drug therapies, only 37% of patients attain adequate blood glucose control [4], suggesting that there is an unmet need for agents that can effectively control blood glucose. Additionally, some of the existing glucose-lowering agents have several shortcomings, such as weight gain (thiazolidinediones, SUs, and insulin), hypoglycemia (SUs, glinides, and insulin), and gastrointestinal side effects (metformin and α-glucosidase inhibitors) [5].

Ipragliflozin is a novel sodium-glucose cotransporter 2 (SGLT2) selective inhibitor that inhibits SGLT2-mediated glucose reabsorption in the renal proximal tubules and facilitates glucose excretion in urine, thereby lowering blood glucose levels [6, 7]. During the drug development process, several randomized controlled trials demonstrated the efficacy and safety of ipragliflozin alone and in combination with other glucose-lowering agents [8,9,10,11,12,13]. Glucagon-like peptide-1 (GLP-1) receptor agonists are incretin-based, injectable antidiabetic agents that act directly on glucose-dependent pancreatic islet cell hormone secretion and improve fasting and postprandial blood glucose control without risk of hypoglycemia. GLP-1 receptor agonists also promote body weight loss through the stimulation of GLP-1 receptors in hypothalamic satiety centers [14]. GLP-1 receptor agonists are introduced when patients cannot achieve their goals for glycemic control by means of diet and exercise therapies and/or oral glucose-lowering agents [15].

The aim of this study was to evaluate the efficacy and safety of ipragliflozin treatment in combination with GLP-1 receptor agonists in Japanese patients with T2DM who did not achieve adequate glycemic control with GLP-1 receptor agonist therapy during a minimum period of 6 weeks prior to enrollment.

Methods

Study Design

This multicenter (Electronic Supplementary Material 1) open-label study consisted of three periods: a 4-week washout period (only for patients using glucose-lowering agents other than GLP-1 receptor agonists and SUs), a 6-week observation period, and a 52-week open-label treatment period. During the observation period, we confirmed the stability of glycosylated hemoglobin (HbA1c). Following the observation period, patients were registered and began the open-label treatment period. The dose of the study drug was increased according to the dose-escalation criteria defined in this study. The 52-week open-label treatment period comprised an initial 20-week period of administration of ipragliflozin at a fixed dose of 50 mg/day. Patients with an HbA1c of > 7.0% at week 16 (considered to be poor responders to the 50-mg ipragliflozin dose) were eligible for a dose increase to 100 mg/day starting on week 20. In the following 32 weeks, patients received ipragliflozin at either 50 mg or 100 mg/day. The study design is shown in Fig. 1.

Fig. 1
figure 1

Study design. GLP-1RA Glucagon-like peptide-1 receptor agonist, IPRA ipragliflozin, SU sulfonylurea

The study was conducted at 19 sites in Japan. All procedures performed in the study were in accordance with the ethical standards of the institutional review board of each site and with the 1964 Helsinki declaration and its later amendments. Additionally, the study complied with all relevant laws and regulations, including Good Clinical Practice and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines. Informed consent was obtained from all individual participants included in the study. This study was registered at ClinicalTrials.gov (identifier: NCT02291874).

Study Eligibility and Withdrawal

The inclusion criteria were as follows: age ≥ 20 years; diagnosis of type 2 diabetes ≥ 12 weeks before enrollment; prescription of a stable dose/regimen of a GLP-1 receptor agonist or concomitant prescription of a stable dose/regimen of a GLP-1 receptor agonist and SU for ≥ 6 weeks; HbA1c ≥  7.5% and ≤ 10.5%, with a maximum change in HbA1c of ± 1% at visit 1 (week − 6) and visit 2 (week − 2); body mass index (BMI) of between 20.0 and 45.0 kg/m2; and fasting plasma glucose (FPG) level of ≥ 126 mg/dL at visit 2 (week − 2) for those receiving SU therapy.

The main exclusion criteria were as follows: diagnosis of type 1 diabetes mellitus; urinary symptoms (dysuria, anuria, oliguria, and urinary retention); history of recurrent urinary tract or genital infection; proliferative retinopathy; renal disease; history of pancreatitis or cerebrovascular or cardiovascular diseases; chronic disease(s) that required continuous use of non-topical corticosteroids or immunosuppressants; severe infections; malignant tumors; alcoholism or other addictions; unstable psychiatric disorder; women with child-bearing potential not using contraceptives appropriately; history of allergy to ipragliflozin and/or similar drugs; previous participation in a clinical study or postmarketing surveillance within 12 weeks of enrollment; and patients who were unable or unwilling to adhere to the study procedures.

Patients could be withdrawn at any time during the study for a number of reasons, including safety concerns and severe hypoglycemia (hypoglycemic coma, convulsions, or other conditions requiring infusion or injection of glucose or glucagon). Additionally, patients were withdrawn if their HbA1c was > 8.5% on two consecutive visits from week 24 onwards and if the FPG level exceeded 270 mg/dL on two consecutive measurements.

Treatments

Patients underwent liraglutide monotherapy or treatment with liraglutide or other GLP-1 receptor agonist in combination with an SU at a constant dose/dose regimen for at least 6 weeks before visit 1. Visit 1 (week − 6) was then followed by the 6-week observation period, registration, and enrollment into the open-label treatment period. At the beginning of the 20-week open-label treatment period, all patients received 50 mg/day of ipragliflozin. At week 20, the ipragliflozin dose could be increased to 100 mg/day in patients whose HbA1c was ≥ 7.0% (poor responders) and for whom the investigators considered there were no safety concerns. Treatment was discontinued in patients whose HbA1c was > 8.5% at two consecutive visits from visit 10 (week 24) onwards. From the observation period to the end of the treatment period, the type or dose/dose regimen of GLP-1 receptor agonists and SU could not be changed. Once the dose of ipragliflozin was escalated, the patient continued to receive ipragliflozin at the escalated dose (100 mg/day), in principle, until the end of the treatment period. However, if safety concerns were raised after the dose increase, the dose could be reduced to 50 mg/day, but no further dose adjustment was allowed after the dose reduction.

Patients performed self-monitoring of fasting blood glucose every morning, or if they felt symptoms of hypoglycemia, and recorded the values in their diary. Treatment compliance was assessed by the investigator based on the patient diary, dispensed study drugs, number of collected study drugs, and number of lost study drugs. The use of glucose-lowering agents and insulin was prohibited, except for the use of ipragliflozin, GLP-1 receptor agonists, and SUs. In Japan, liraglutide is approved as monotherapy or as combination therapy with SUs, whereas other GLP-1 receptor agonists are approved for use only in combination with SUs. Because the Japanese clinical guidelines do not recommend any specific class of antidiabetic drug (including biguanides) as the first-line therapy, metformin was not included among the permitted concomitant oral antidiabetic drugs in this study. Temporary or topical use of corticosteroids or immunosuppressants was allowed.

Endpoints and Assessments

The changes from baseline (week 0) in HbA1c, FPG, fasting insulin, leptin, adiponectin, glucagon, body weight, waist circumference, homeostasis model assessment (HOMA)-R, HOMA-beta, and self-monitored blood glucose (SMBG) values recorded in the patient diary were examined. HbA1c, FPG, fasting insulin, leptin, adiponectin, and glucagon levels were measured by LSI Medience Corporation (Tokyo, Japan). For HbA1c levels, National Glycohemoglobin Standardization Program values were used. SMBG was performed seven times a day (fasting after waking up, 1 h after the start of breakfast, before lunch, 1 h after the start of lunch, before dinner, 1 h after the start of dinner, and before bedtime) for 3 days per week before each scheduled visit, and the measured value, time of measurement, start time of each meal, and dinner end time were recorded in the diary.

Safety was assessed in terms of vital signs, treatment-emergent adverse events (TEAEs), and laboratory tests. TEAEs were defined as AEs observed after the first administration of ipragliflozin and were classified according to system organ class and preferred term (MedDRA version 1.61; https://www.meddra.org/how-to-use/support-documentation); their relationship to the study drug, seriousness, and severity were evaluated.

Statistical Analysis

An estimated sample size of 100 patients (approximately 70 patients to receive ipragliflozin in combination with a GLP-1 receptor agonist and approximately 30 patients to receive ipragliflozin in combination with a GLP-1 receptor agonist and SU) was planned based on the Guidelines for Clinical Evaluation of Oral Antihyperglycemic Drugs (Notification no. 0709-1 of the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, dated July 9, 2010) [16], in which 50–100 patients per group are recommended to ensure a sufficient number of patients to evaluate the safety of the test drug.

The study analysis sets were the full analysis set (all patients who received at least one dose of ipragliflozin, and in whom at least one efficacy variable was measured after administration of ipragliflozin) and the safety analysis set (all patients who received at least one dose of ipragliflozin). Overall data were analyzed, and data for both subgroups separately: 50/50 mg group (in which the dose of ipragliflozin was maintained at week 20 because of sufficient efficacy or safety concerns) and the 50/100 mg group.

Missing data were not imputed, except for the month of T2DM diagnosis and partial onset dates of AEs. Baseline characteristics were summarized descriptively using mean ± standard deviation (SD) or the number and percentage of patients for continuous and categorical variables, respectively. Efficacy data were analyzed descriptively in terms of the mean ± SD values at each time point together with the mean changes from baseline to each time point. The mean values and changes in efficacy variables from baseline to the end of treatment using the last observation carried forward were also calculated. TEAEs were presented as the number and percentage of patients in each treatment group. The statistical analyses were performed by Astellas Pharma Inc. using Version 9.2 or later of Windows SAS® (SAS Institute Inc., Cary, NC, USA).

Results

Patients

The baseline characteristics of patients are shown in Table 1. Overall, the majority of patients were male (72/103, 69.9%), had a mean (± SD) age of 53.4 ± 10.5 years at the time of consent, BMI of 28.09 ± 4.15 kg/m2, HbA1c of 8.81 ± 0.89%, FPG of 185.9 ± 44.2 mg/dL, and estimated glomerular filtration rate of 86.69 ± 18.39 mL/min/1.73 m2. More than one-half of the patients (57 [55.3%]) had diabetes for < 120 months (10 years). The majority (90/103 [87.4%]) had been treated with liraglutide monotherapy, with only 13/103 (12.6%) treated with liraglutide or another GLP-1 receptor agonist in combination with an SU. The percentage of patients who underwent washout of glucose-lowering agents other than GLP-1 receptor agonists and SU agents was 18.4% (19/103). When both groups were compared, the 50/50 mg group had numerically lower baseline body weight, BMI, FPG, and HbA1c values, and shorter diabetes mellitus duration compared with the 50/100 mg group.

Table 1 Baseline characteristics

As shown in the patient flow diagram (Fig. 2), a total of 103 patients received ipragliflozin 50 mg/day, three of whom discontinued the treatment by week 20 because of an AE, and 100 of whom continued ipragliflozin 50 mg/day until week 20. Of these, 67 patients had not achieved adequate glycemic control, and their ipragliflozin dose was increased to 100 mg/day (50/100 mg group), while 33 patients maintained the initial ipragliflozin dose (50/50 mg group). Among patients in the 50/50 mg group, 32 completed the study, and one patient discontinued because of lack of efficacy. Among those in the 50/100 mg group, two patients underwent a dose decrease to 50 mg/day after week 20 because of AEs (one patient presented fatigue and the other, pollakiuria); both patients completed the study. Of the remaining 65 patients in the 50/100 mg group, 49 patients completed the study and 16 discontinued (14 for lack of efficacy, 1 for an adverse event, and 1 patient withdrew voluntarily).

Fig. 2
figure 2

Flow chart of patient disposition during the study

HbA1c, FPG, and SMBG

The mean (± SD) change in HbA1c from baseline to end of treatment was − 0.92 ± 0.80% (95% confidence interval [CI] − 1.07, − 0.76]) in all ipragliflozin-treated patients (n = 103). The mean changes in HbA1c from baseline to week 20 and from baseline to end of treatment were − 1.18 ± 0.66% and − 0.84 ± 0.75%, respectively, in the 50/50 mg group and − 0.95 ± 0.71% and − 0.97 ± 0.83%, respectively, in the 50/100 mg group (Table 2). These values reflect an increase of 0.33% from week 20 to end of treatment in the 50/50 mg group, but a decrease of 0.02% in the 50/100 mg group.

Table 2 Efficacy variables

The time courses of HbA1c and changes in HbA1c from baseline in each dose subgroup are shown in Fig. 3a, b. The 50-mg dose was administered until week 20, and HbA1c decreased in both subgroups. In the 50/50 mg group, the dose remained at 50 mg/day at week 20, and HbA1c slightly increased until week 52. In the 50/100 mg group, the dose was increased to 100 mg/day at week 20, and HbA1c further decreased until week 36, with a subsequent slight increase until week 52.

Fig. 3
figure 3

a Time course of glycosylated hemoglobin (HbA1c) of patients in each dose subgroup, b time course of changes in HbA1c from baseline to end of treatment of patients in each dose subgroup. Data are shown as the mean and standard deviation (SD) (full analysis set) for all patients who received ipragliflozin. Error bars: SD. The number of patients at each time point is shown below the x-axis. EOT End of the treatment period, LOCF last observation carried forward

The mean (± SD) change in FPG from baseline to the end of treatment was − 38.9 ± 39.0 mg/dL (95% CI − 46.5, − 31.3) (Table 2). The time courses of FPG and changes in FPG from baseline in each dose subgroup are shown in Fig. 4a, b. In each dose subgroup, FPG decreased rapidly within 2 weeks of starting treatment with ipragliflozin. In the 50/50 mg group, the FPG level continued to decrease gradually up to week 20 and remained almost unchanged thereafter. In the 50/100 mg group, the FPG level continued to decrease gradually up to week 32 and remained almost unchanged thereafter. The decrease in FPG until week 52 was more marked in the 50/100 mg group.

Fig. 4
figure 4

a Time course of fasting plasma glucose (FPG) of patients in each dose subgroup, b time course of changes in FPG from baseline to end of treatment of patients in each dose subgroup. Data are shown as the mean and SD (full analysis set) for all patients who received ipragliflozin. Error bars: SD. The number of patients at each time point is shown below the x-axis

The mean (± SD) change in SMBG from baseline to the end of treatment in all patients was − 38.9 ± 41.3 mg/dL in the fasting state, − 52.5 ± 61.2 mg/dL 1 h after breakfast, − 47.3 ± 53.5 mg/dL before lunch, − 51.3 ± 69.1 mg/dL 1 h after lunch, − 35.9 ± 46.8 mg/dL before dinner, − 40.9 ± 63.7 mg/dL 1 h after dinner, and − 54.9 ± 65.3 mg/dL before bedtime (Table 2). Figure 5 shows the SMBG profile in each dose subgroup. A sustained reduction from baseline in SMBG was observed over the 52 weeks of treatment in both ipragliflozin dose subgroups at all measurement time points. The same sustained reduction in SMBG was reflected by the changes in the seven-point SMBG profile from baseline to the end of treatment in both ipragliflozin dose subgroups, as shown in Fig. 6.

Fig. 5
figure 5

Seven-point self-monitored blood glucose (SMBG) profile at baseline and EOT in each dose subgroup. Error bars: SD

Fig. 6
figure 6

Changes in seven-point SMBG profile from baseline to end of treatment in each dose subgroup. Error bars: SD

Metabolic Parameters

Table 2 shows the changes in body weight, waist circumference, and metabolic parameters from baseline to the end of treatment in all ipragliflozin-treated patients and according to the dose of ipragliflozin used. The mean (SD) change in body weight from baseline to the end of treatment in all patients was − 2.69 ± 2.39 kg (95% CI − 3.16, − 2.22). The mean change in body weight from baseline to the end of treatment in the 50/50 mg group was − 2.53 ± 1.48 kg and that in the 50/100 mg group was − 2.77 ± 2.76 kg. The time courses of body weight and changes in body weight from baseline in each dose subgroup are shown in Fig. 7a, b. During the course of the 52-week treatment, body weight decreased progressively in each ipragliflozin dose subgroup. In the 50/50 mg group, a marked decline in body weight was observed up to week 16, after which it showed a tendency to increase, and then remained approximately stable up to week 52. In the 50/100 mg group, body weight declined more gradually, with a further reduction after the dose was increased to 100 mg/day at week 20.

Fig. 7
figure 7

a Time course of body weight of patients in each dose subgroup, b time course of changes in body weight from baseline to end of treatment of patients in each dose subgroup. Data are shown as the mean and SD (full analysis set) for all patients who received ipragliflozin. Error bars: SD. The number of patients at each time point is shown below the x-axis

Glucagon increased from baseline to the end of treatment; the increase was 23.1 ± 27.6 pg/mL (95% CI 17.7, 28.5) in all patients. Leptin was unchanged in all patients (− 0.19 ± 4.29 ng/mL; 95% CI − 1.03, 0.65). Adiponectin increased in all patients (0.98 ± 1.63 μg/mL; 95% CI 0.66, 1.30) (Table 2).

Safety

Treatment-emergent adverse events occurring in all patients who received ipragliflozin are shown in Table 3. TEAEs occurred in 77.7% (80/103) of patients treated with ipragliflozin. Overall, 46.6% (48/103) of patients experienced drug-related TEAEs. Serious TEAEs occurred in 3.9% (4/103) of patients and included glaucoma, nasopharyngitis, cerebral infarction, and sleep apnea syndrome (in one patient each). Hospitalization was required in three cases (glaucoma, nasopharyngitis, and sleep apnea syndrome), and cerebral infarction was regarded as an event of medical significance. Of these, glaucoma and nasopharyngitis were considered by the investigator as not related to the study drug. TEAEs leading to permanent discontinuation occurred in 3.9% (4/103) of patients and included constipation, hypoglycemia, cerebral infarction, and rash (in one patient each). The latter patient developed a rash on day 29 after starting treatment, which disappeared completely (resolved) by day 50. The patient continued medical treatment for the rash up to day 47. The severity of the rash was mild, and it was considered as “probably related” to the study treatment. By preferred term, the most common drug-related TEAEs in all patients were pollakiuria (9.7% [10/103]), hypoglycemia (8.7% [9/103]), constipation (6.8% [7/103]), and thirst (5.8% [6/103]). Administration of ipragliflozin was not associated with any clinically significant changes in laboratory variables or vital signs, except for increased blood ketone bodies. No deaths were reported during this study.

Table 3 Treatment-emergent adverse events

Discussion

Given the lack of efficacy and safety data on ipragliflozin when used in combination with GLP-1 receptor agonists for the treatment of T2DM in Japan, we conducted this open-label, clinical study to evaluate the efficacy and safety of ipragliflozin treatment (52 weeks, 50 or 100 mg/day) in combination with GLP-1 receptor agonists. We also assessed the persistence of the efficacy of treatment with ipragliflozin 50 mg/day and the effect of a dose increase of ipragliflozin to 100 mg/day in this patient sample.

The improvement in glycemic control in patients treated with ipragliflozin was maintained from baseline up to week 52. The mean HbA1c and FPG levels decreased immediately after initiation of the study treatment, and the lowered values were sustained until week 52. Consistent with these observations, a sustained reduction from baseline in SMBG was observed over 52 weeks for all time points, which indicates that ipragliflozin exhibits glucose-lowering effects on both fasting and postprandial blood glucose levels. These results are consistent with those of previous clinical trials of ipragliflozin alone or in combination with other oral glucose-lowering agents [8,9,10,11,12,13, 17,18,19].

Mean body weight steadily decreased from baseline up to week 16, and the decrease was maintained throughout the 52-week treatment. This is a relevant clinical finding because weight gain is a shortcoming of several existing therapies for diabetes, including insulin [5]. Weight reduction is a strength of GLP-1 receptor agonist therapy [20]. However, in this study, this weight-reducing effect was further reinforced by the use of ipragliflozin, which promotes urinary calorie loss [21]. These effects on glycemic control and body weight are consistent with the results of recent studies on dapagliflozin [22] and luseogliflozin [23] added on to therapy with a GLP-1 receptor agonist in Japanese patients. The use of concomitant SUs in some patients may have influenced the evaluations of weight change. However, because the number of patients in this group was limited (13 patients), a separate subanalysis of body weight change in this group was not performed.

In the present study, we further showed that the dose increase of ipragliflozin to 100 mg/day resulted in better glycemic control and weight reduction in patients for whom the 50-mg dose was insufficient. Absolute reductions in either HbA1c or body weight were larger in patients in the 50/100 mg group than in those in the 50/50 mg group. This may be the result of differences in baseline HbA1c and body weight. Nonetheless, HbA1c and body weight were maintained in the 50/100 group compared with the tendency of these parameters to increase in the 50/50 group after 20 weeks. This finding suggests that increasing the ipragliflozin dose to 100 mg/day is a feasible option when sufficient glycemic control or weight reduction is not achieved after several months of treatment with ipragliflozin 50 mg/day.

In terms of safety, the incidence of TEAEs was 77.7% (80/103) and that of drug-related TEAEs was 46.6% (48/103); all TEAEs were mild or moderate in severity. The rate of serious TEAEs was low (4 patients [3.9%]), and all serious TEAEs were mild in severity.

As the pharmacological action of ipragliflozin involves increased urinary glucose excretion, particular attention was focused on hypoglycemia, urinary tract infection, genital infection, and effects on body fluid volume and electrolytes. These events were noted, but all were mild in severity and resolved without the need for specific treatment. Of the nine patients who experienced hypoglycemia-related events, only one had to permanently discontinue the study.

The most common drug-related TEAEs were pollakiuria, hypoglycemia, constipation, and thirst. The gastrointestinal drug-related TEAEs reported are in line with the characteristics of GLP-1 receptor agonist therapy; these typically include nausea in approximately  15–20% of patients, as well as vomiting, constipation, and diarrhea (approx. 5% each) [24]. The TEAEs that did occur in the present study have been previously reported in other clinical trials of ipragliflozin [8,9,10,11,12,13, 17, 19]. Although we did not observe any striking differences in the incidence of TEAEs between our study and previous clinical trials, we did note fewer cases of cystitis and more cases of thirst. Although SGLT2 inhibitors have been associated with urinary tract infections in some studies, this finding is not consistent among all trials [24]. The lower incidence observed in our study compared with others may be attributed to cultural differences in the Japanese lifestyle, such as bathing practices. Similarly, the incidence of thirst may have been influenced by the hot and humid summer weather in Japan. In summary, no previously unreported TEAEs were found when ipragliflozin was used in combination with GLP-1 receptor agonists.

A recently published review article by DeFronzo [24] discussed the potential benefits of the combined use of SGLT2 inhibitors and GLP-1 receptor agonists on metabolic–cardiovascular–renal disease in patients with T2DM. Such benefits of this combination therapy may outweigh the resulting AEs, which in this study were mostly mild in severity. However, further safety data are required to determine whether the observed AEs are a result of a class effect.

This study had several limitations, such as the open-label study design and consequent lack of a control group. Additionally, all analyses reported here were performed in an exploratory manner, without formal statistical tests. The present results can only be generalized to the Japanese T2DM population, and there are some inconsistencies between Japanese and international guidelines in the recommended drugs for the treatment of type 2 diabetes. A high proportion of patients completed the study, which may be a reflection of the benefits of SGLT2 inhibitors (e.g., weight loss and glycemic improvement) during the treatment of type 2 diabetes.

Ipragliflozin treatment for 52 weeks in combination with a GLP-1 receptor agonist was found to be clinically and significantly efficacious in reducing HbA1c, FPG, and SMBG in patients with type 2 diabetes who had inadequate glycemic control with GLP-1 receptor agonist therapy. The mean body weight steadily decreased from baseline up to week 16, and the decrease was maintained until the end of the treatment. Increasing the daily dose of ipragliflozin to 100 mg led to better glycemic control in patients for whom efficacy was insufficient at a dose of 50 mg. No previously unreported safety concerns were identified.

Conclusions

The results from this study suggest that ipragliflozin can be recommended as a well-tolerated and effective add-on therapy to a GLP-1 receptor agonist for glycemic control in T2DM patients. Because both SGLT2 inhibitors [25] and GLP-1 receptor agonists [26] have been shown to be beneficial for cardiovascular risks, this combination therapy could be a favorable choice for treatment of T2DM.