Multicenter, open label, randomized controlled superiority trial for availability to reduce nocturnal urination frequency: The TOP‐STAR study

ABSTRACT

Aim

Nocturia impairs the quality of life in patients with type 2 diabetes mellitus. Although sodium glucose co‐transporter 2 inhibitors (SGLT2i) such as tofogliflozin increase urine volume, their impact on nocturia, in conjunction with dietary salt restriction, is less clear.

Materials and Methods

This multicenter, open‐label, randomized, parallel‐group trial included 80 subjects with type 2 diabetes and nocturia. The patients were divided into two groups: one receiving tofogliflozin, the shortest half‐life, without salt restriction, and the other receiving both tofogliflozin and dietary salt restriction. The primary endpoint was nocturia frequency at 12 weeks. The secondary outcomes included changes in daytime urination frequency, urine volume, and home blood pressure.

Results

At 12 weeks, there were no significant differences in nocturia changes between both groups. Nocturia frequency did not change in the tofogliflozin without salt restriction group from 1.5 ± 0.8 to 1.3 ± 1.1 times per night (P = 0.297), and significantly decreased from 1.6 ± 1.0 to 1.3 ± 0.7 times per night in the tofogliflozin and dietary salt restriction group (P = 0.049). There was a trend toward increased urine volume and frequency during the daytime in the group with salt restriction, indicating a time‐shift effect of the short half‐life tofogliflozin and salt restriction on urinary time.

Conclusions

The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half‐life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes.

The effect of tofogliflozin, an SGLT2i with the shortest half‐life, on the frequency of nocturia in patients with T2D was found that the frequency of nocturia did not increase upon tofogliflozin administration. Particularly, combining tofogliflozin administration with dietary salt restriction significantly reduced nocturia.

INTRODUCTION

Nocturia refers to frequent urination at night, the requirement to wake up more than once during the night to urinate ¹ . In Japan, the frequency of nocturia (one or more times) increases with age, reaching 83.8% in men and 76.6% in women in individuals in their 60s ² . Age, diabetes, hypertension, stroke, heart disease, and obesity have been shown to be associated with nocturia ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ . In particular, it has been reported that 40% of patients with diabetes have nocturia more than twice ⁹ , ¹⁰ . In our KAMOGAWA‐DM cohort study ¹¹ , 396 had nocturia. Furthermore, in a questionnaire on the frequency of nocturia administered to 396 of patients, 80% urinated at least once at night and 40% urinated more than twice at night. Thus, nocturia is a common condition in patients with type 2 diabetes mellitus.

In addition, Hashimoto et al. ¹² , reported that the decreased quality of life in Japanese patients with type 2 diabetes was caused by disturbed sleep symptoms, with arousal due to nocturia. Against this backdrop, sodium glucose co‐transporter 2 inhibitors (SGLT2i) are increasingly being prescribed, as their preventive effects against cardiac and renal failure are being confirmed, in addition to their effects in improving glycemic control, and decreasing fat mass ¹³ , ¹⁴ . On the other hand, in Japan, the Committee on the Appropriate Use of SGLT2i was established due to concerns about adverse events, such as dehydration, caused by the diuretic effect of SGLT2i since their initial launch. The committee issued a “Recommendation on the Appropriate Use of SGLT2 Inhibitors” on June 13, 2014, and issued a warning against their use ¹⁵ . In fact, frequent urination and polyuria have been cited as reasons for discontinuation of SGLT2i ¹⁶ . Moreover, our group previously revealed that the main reasons for discontinuing SGLT2i in patients with Japanese type 2 diabetes was the frequent urination ¹⁷ .

Among these SGLT2i, tofogliflozin, which has a short half‐life in the blood, in addition to improving glycemic control, may promote urinary glucose excretion during the day without exacerbating nocturia and may correct nocturia by improving hyperglycemia and hypertension ¹⁸ . Although controversial, SGLT2i have been reported to increase sodium excretion ¹⁹ , and sodium retention is thought to exacerbate nocturia via non‐dipper‐type nocturnal hypertension, and sodium excretion has been shown to potentially improve this ²⁰ . Although sodium retention and non‐dipper type nocturnal hypertension are also factors that exacerbate heart failure, some SGLT2i have been reported to have a preventive effect on heart failure ¹⁴ .

However, to correct nocturia and to prevent its exacerbation, salt restriction must be considered in addition to medications. It has been shown that reducing salt intake can decrease nocturnal voiding frequency, nocturnal urine volume, and the nocturnal polyuria index, and it is recommended that patients with nocturnal polyuria be referred to salt restriction ²¹ .

In an observational study conducted in Japan, nocturia frequency, nocturnal urine volume, and nocturnal polyuria index were evaluated after 12 weeks of dietary guidance in patients with at least one degree of nocturia who exceeded the maximum daily salt intake (8 g for men and 7 g for women). In this observational study, salt restriction instructions were provided every 4 weeks, and the successful group reported an improved nocturnal voiding frequency, urine volume, and nocturnal polyuria index ²¹ . In contrast, 69.5% of the patients were unable to comply with salt restriction, and nocturia did not improve in these patients. Ushigome et al. ²² also reported difficulties in salt restriction by nutritionists, with salt intake reductions of 0.8 (0.2–1.4) g at 2 months and 0.7 (0.1–1.3) g at 6 months.

As mentioned above, the components of nocturia are varied; however, nocturnal hyperglycemia, excessive salt intake, nocturnal hypertension (especially non‐dipper type nocturnal hypertension), and heart failure are considered risks for nocturia ²⁰ , ²³ . As noted above, it is known that salt restriction can improve nocturia; however, no study to date has evaluated the effects of salt restriction in combination with SGLT2i on nocturia. Thus, we evaluated the effect of tofogliflozin, the shortest half‐life SGLT2i, on the frequency of nocturia in patients with type 2 diabetes and its association with salt restriction instruction.

MATERIALS AND METHODS

Study population and study design

TOP‐STAR was designed as an exploratory study, and no prior studies have reported the effect of tofogliflozin on nocturia in patients with type 2 diabetes or the efficacy of tofogliflozin, with or without dietary sodium restriction on nocturia. The detailed protocol of the TOP‐STAR study is shown in Appendix  S1 ²⁴ . Inclusion criteria were patients with type 2 diabetes aged 20 to 90 with nocturia more than once, and exclusion criteria were patients who had used SGLT2i for at least 3 months prior to the consent, patients who had already been instructed by a registered dietitian to limit salt intake or patients with an estimated sodium intake of <6 g/day by urinalysis at the time of obtaining consent.

This was a multicenter, open‐label, randomized, exploratory, prospective, interventional study with randomized assignment that was conducted in 18 research institutions. The minimum number of patients required for this study was calculated to be 36 patients per group by using data assuming a Poisson distribution ²⁴ . 80 patients with type 2 diabetes and nocturia were included in the study and randomly stratified into two groups (Group A was the group receiving tofogliflozin without salt restriction). Randomization was performed using a computer‐generated program by EviPRO Co., Ltd (Tokyo, Japan). The study participants were orally administered 20 mg tofogliflozin once a day, before or after breakfast. The duration of tofogliflozin administration was 12 weeks (9–14 weeks) (Group B was the group receiving tofogliflozin with dietary sodium restriction). In addition to the oral administration of 20 mg of tofogliflozin once a day before or after breakfast, a nutritionist provided instructions once on sodium restriction, with a target sodium intake of 6 g/day. The duration of tofogliflozin treatment was 12 weeks (9–14 weeks), and SGLT2i treatment was initiated on day 0 of the observation period. The study participants were requested to visit the research institutions at weeks 0 and 12 after they provided informed consent. All patients were advised to maintain adequate hydration to prevent dehydration, avoiding both excessive fluid intake and excessive water restriction. The prescribed energy intake was 25–35 kcal/kg/day based on physical activity levels multiplied by the target weight. Protein intake was restricted to 0.8–1.0 g/kg/day for patients with stage 3 diabetic nephropathy and 0.6–0.8 g/kg/day with stage 4 diabetic nephropathy.

Ethics approval and consent to participate

This study was registered with the Japan Clinical Trial Registry (jRCTs051210212) and was approved by the ethics committees of the Kyoto Prefectural University of Medicine (CRB5200001). This study was conducted in accordance with the principals of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to their inclusion in this study.

Observations

A baseline examination was performed before the intervention. The details of the observations and schedule are provided in Appendix  S1 . Nocturia is defined as waking up to urinate once or more times during the night ¹ . In this study, the number of nocturnal urinations was also counted from the urinary diary. The nocturnal index means the percentage of nocturnal urine volume of the total daily urine volume. The nocturnal index (%) was calculated as follows: 100× (urine volume at night/daily urine volume).

Generally, the participants visited and received blood and urinalysis at every visit to the research institution. Additionally, nocturnal home blood pressure measurements were taken three times a day for 5 days. Urinary frequency was recorded for 7 days, and the urine volume was measured using a measuring cup for 3 days. Also, the Japanese version of the Diabetes Treatment Satisfaction Questionnaire, status version (DTSQs) ²⁵ , Diabetes Diet‐Related Quality of Life Revised (DDRQOL‐R) ²⁶ , Brief‐type Self‐administered Diet History Questionnaire (BDHQ) ²⁷ , and Core Lower Urinary Tract Symptoms (CLSS) ²⁸ scores were assessed using patient questionnaires.

Outcomes

The primary objective of this study is to assess the impact of tofogliflozin on nocturia in patients with type 2 diabetes and to investigate the efficacy of tofogliflozin with or without dietary sodium restriction on nocturia at 12 weeks after interventions.

Statistical analysis

Differences between the groups were analyzed as follows: the baseline clinical characteristics of the groups were compared using one‐way anova and Tukey's honestly significant difference test for continuous variables, and the Fisher's exact test for categorical variables. Also, one‐sample t‐tests for comparison within groups and two‐sample t‐tests for comparison between groups were performed for the amount of change. The primary and secondary endpoints were analyzed using the full analysis set, with a two‐sided significance level set at 5%. The individual responsible for the statistical analysis was tasked with preparing a separate statistical analysis plan and specifying the details of the statistical methods, including data handling. The primary outcome was the frequency of nocturia at 12 weeks, and the differences between groups were evaluated to determine statistical significance. A Poisson regression analysis (generalized linear model assuming a Poisson distribution) was conducted, with the group as a fixed effect, and the allocation adjustment factors and baseline nocturnal voiding days as covariates. This tested the null hypothesis that nocturnal voiding days are the same across groups. Summary statistics (number of cases, minimum, median, maximum, mean, and standard deviation) were calculated for each time point and group. Regarding the primary endpoint, the frequency of urination during the day was assessed for statistical significance using a Poisson regression analysis, with the group as the fixed effect, and the allocation adjustment factor, and baseline value as covariates. For the other change endpoints, group differences were evaluated using analysis of covariance, with the group as the fixed effect and allocation adjustment factors and baseline values as covariates. Additionally, summary statistics of the measurements and changes at each time point for each endpoint were calculated for each group. Safety endpoints, including the incidence of adverse events and diseases, were also analyzed.

RESULTS

Study participants

Eighty participants were recruited from March 30, 2022 to April 30, 2023, and 34 and 31 patients were included in the analysis in groups A and B, respectively, because some patients withdrew consent before the study began. Patients who withdrew their consent agreed to their data up to the time of consent withdrawal being included in the full analysis set. Moreover, two patients who discontinued participation met the following exclusion criteria: low blood pressure (<100/60 mmHg). A flowchart of the study subjects is shown in Figure 1.

Figure 1.

Flowchart of the study subjects. The number of participants enrolled, the number in the FAS, the number who withdrew consent, the number who did not receive any research treatment since enrollment, the number with at least one primary endpoint, and the number who violated the inclusion criteria are shown. Group A, group receiving tofogliflozin without salt restriction; Group B, group receiving tofogliflozin with dietary sodium restriction.

Group A received tofogliflozin without salt restriction, and group B received a combination of tofogliflozin and salt restriction. The results showed no significant difference in age, most diabetes medications, and other baseline characteristics between the two groups (Table 1). There was no difference between the two groups in the use of medications with diabetes or diuretics. Only the frequency of α‐glucosidase inhibitor use differed (P = 0.047), but the number of participants in both groups was small: one (2.9%) in group A and six (19.4%) in group B. Also, no other factors were found that could have influenced the result of the study.

Table 1.

Baseline characteristics of study participant of full analysis set group

	Group A	Group B	P value
n	34	31
Age, years	70.4 ± 11.0	69.1 ± 8.7	0.62
Male, %	67.6	67.7	1.00
Duration of diabetes, years	13.2 ± 8.1	15.5 ± 9.4	0.30
Height, cm	162.5 ± 8.9	165.4 ± 8.9	0.19
Body weight, kg	65.2 ± 12.0	68.7 ± 13.2	0.26
Body mass index, kg/m2	24.6 ± 3.9	25.0 ± 3.5	0.69
HbA1c, %	7.4 ± 0.9	7.2 ± 0.8	0.46
Diabetic nephropathy (stage 1/stage 2/stage 3/stage 4/stage 5)	20/8/5/1/0	22/6/1/2/0	0.42
Diabetic retinopathy, %	6.1	17.2	0.32
Diabetic neuropathy, %	12.9	14.3	1.00
Coronary artery disease, %	0.0	3.2	0.48
Insulin, %	17.6	12.9	0.74
Sulfonylurea, %	14.7	16.1	1.00
Metformin, %	44.1	54.8	0.46
Thiazolidine, %	0.0	6.5	0.22
α‐Glucosidase inhibitor, %	2.9	19.4	0.047
Dipeptidyl peptidase‐4 inhibitor, %	38.2	51.6	0.32
GLP‐1 agonist, %	35.3	25.8	0.43
Antihypertension medication, %	67.6	64.5	0.80
Ca antagonist, %	38.2	38.7	1.00
ACE inhibitors, %	5.9	0.0	0.49
ARB, %	50.0	48.4	1.00
Diuretic, %	0.0	3.2	0.48
Beta‐blocker, %	5.9	12.9	0.41
Alpha‐blocker, %	0.0	6.5	0.22
Statin, %	44.1	54.8	0.46

Data are expressed as mean ± SD, number or %. Comparisons were carried out using one‐way anova and Tukey's honestly significant difference test for continuous variables, and the Fisher's exact test for categorical variables. Group A, group receiving tofogliflozin without salt restriction; Group B, group receiving tofogliflozin with dietary sodium restriction.

Primary endpoint

The nocturia frequency at the baseline was 1.5 ± 0.8 times/day in group A and 1.6 ± 1.0 times/day in group B. After the intervention, the nocturia frequency was 1.3 ± 1.1 times/day in group A (P = 0.297) and 1.3 ± 0.7 times/day in group B (P = 0.049). The nocturia frequency significantly decreased only in group B; no significant difference between the two groups was found (P = 0.74). Both the frequency of urination at night and the urine volume at night (P = 0.07) decreased when salt restriction was administered.

Secondary endpoints

Changes in each variable before and after SGLT2i administration were evaluated in groups A and B (Table 2). In group A, the frequency of urination during the day increased significantly, from 7.9 ± 2.2 to 8.3 ± 2.0 times/day (P = 0.04). Group B showed an increasing trend in daily urinary frequency, from 7.0 ± 1.5 to 7.4 ± 1.8 times/day (P = 0.07). There was no significant difference in the frequency of urination during the day between the two groups (P = 0.81). Furthermore, no significant changes in nocturnal urine volume were observed before or after the intervention in either group or between two groups. There was a significant increase in daytime urinary volume (308.3 ± 412.0 mL in group A and 275.3 ± 418.7 mL in group B) after SGLT2i administration. Therefore, the nocturnal index significantly decreased after intervention in both groups (P = 0.013 in group A and P = 0.001 in group B).

Table 2.

Frequency of nocturia and urination during the day after taking tofogliflozin interventions among full analysis set group

Total	Before	After	Change by intervention	P value
Nocturia, time/day
Group A	1.5 ± 0.8	1.3 ± 1.1	−0.14 ± 0.7	0.297
Group B	1.6 ± 1.0	1.3 ± 0.7	−0.27 ± 0.61	0.049
P value	0.82	0.89	0.74
Adjusted mean difference				−0.08 (−0.52, 0.37)
Frequency of urination during the day, time
Group A	7.9 ± 2.2	8.3 ± 2.0	0.5 ± 1.3	0.04
Group B	7.0 ± 1.5	7.4 ± 1.8	0.5 ± 1.3	0.07
P value	0.06	0.08	0.81
Nocturia index, %
Group A	33.5 ± 12.5	27.6 ± 10.1	−6.0 ± 12.6	0.013
Group B	35.2 ± 12.1	29.0 ± 10.1	−7.1 ± 9.4	0.001
P value	0.59	0.61	0.72
Urine volume at night, mL
Group A	475.8 ± 217.7	470.2 ± 211.4	−13.7 ± 216.3	0.73
Group B	613.7 ± 301.4	545.0 ± 264.1	−74.5 ± 195.2	0.07
P value	0.041	0.25	0.29
Urine volume during the day, mL
Group A	934.6 ± 373.9	1257.7 ± 497.7	308.3 ± 412.0	<0.001
Group B	1116.9 ± 383.3	1324.0 ± 429.9	275.3 ± 418.7	0.004
P value	0.06	0.61	0.77
Estimated salt intake from urinary sodium excretion, g
Group A	9.2 ± 3.5	11.1 ± 3.9	2.2 ± 3.7	0.003
Group B	11.8 ± 4.2	12.2 ± 5.7	0.2 ± 5.6	0.89
P value	0.013	0.39	0.13
Urinary sodium excretion, mEq/day
Group A	155.6 ± 59.3	188.3 ± 67.0	37.6 ± 62.5	0.004
Group B	210.6 ± 77.6	198.9 ± 102.9	−18.6 ± 110.7	0.44
P value	0.004	0.65	0.028

Data are expressed as mean ± SD. Summary statistics for the measured value and change for each observation point were calculated for each group, and a two‐sample t‐test for between‐group comparisons was performed for the measured value. One‐sample t‐tests for comparison within groups and two‐sample t‐tests for comparison between groups were performed for the amount of change. The Poisson regression analysis was performed with group as fixed effects, allocation adjustors, and baseline values as covariates, and adjusted mean differences were calculated. Group A, group receiving tofogliflozin without salt restriction; Group B, group receiving tofogliflozin with dietary sodium restriction.

The covariance analysis of the changes in the two groups before and after tofogliflozin administration showed no significant differences in nocturia index, change in urine volume at night, change in urine volume during the day and other urinalysis parameters. Only the change in total urinary sodium excretion was significantly decreased in group B. The blood test results showed that the hematocrit significantly increased after the intervention in both groups (Table 3). On the other hand, γ‐GTP and uric acid (UA) showed significant decreases in both groups. There were significant increases in HDL and β‐hydroxybutyrate levels before and after the intervention in group A. In addition, there were significant decreases in HbA1c and blood glucose levels in group A.

Table 3.

Change in the results of blood tests before and after taking tofogliflozin

Total	Before	After	Change by intervention	P value
AST, IU/L
Group A	24.2 ± 12.5	22.3 ± 6.6	−2.1 ± 8.9	0.18
Group B	22.5 ± 7.1	21.7 ± 6.6	−0.7 ± 6.1	0.53
P value	0.52	0.69	0.48
ALT, IU/L
Group A	24.6 ± 19.1	22.2 ± 14.2	−2.7 ± 10.7	0.16
Group B	21.2 ± 9.8	18.3 ± 7.4	−1.9 ± 5.3	0.06
P value	0.36	0.19	0.73
r‐GTP, IU/L
Group A	30.8 ± 21.8	27.0 ± 19.1	−3.8 ± 10.6	0.049
Group B	31.9 ± 20.1	24.4 ± 13.8	−6.9 ± 12.0	0.004
P value	0.83	0.56	0.28
UA, mg/dL
Group A	5.3 ± 1.3	4.7 ± 1.3	−0.7 ± 0.8	<0.001
Group B	5.5 ± 1.0	5.1 ± 1.4	−0.4 ± 1.0	0.038
P value	0.43	0.26	0.28
HDL, mg/dL
Group A	57.4 ± 12.7	60.5 ± 12.9	3.3 ± 4.1	<0.001
Group B	61.6 ± 20.9	61.2 ± 19.2	0.4 ± 8.8	0.79
P value	0.33	0.86	0.10
LDL, mg/dL
Group A	107.5 ± 40.0	107.8 ± 36.4	1.6 ± 15.1	0.61
Group B	105.6 ± 25.5	106.1 ± 20.7	−2.7 ± 12.5	0.42
P value	0.85	0.86	0.37
TG, mg/dL
Group A	125.0 ± 75.4	122.5 ± 54.2	−11.5 ± 36.6	0.14
Group B	127.8 ± 61.6	133.5 ± 70.2	−8.7 ± 48.8	0.49
P value	0.89	0.54	0.84
eGFR, mL/min/1.73 m2
Group A	66.4 ± 20.9	63.9 ± 16.8	−2.2 ± 8.1	0.13
Group B	59.0 ± 16.2	58.7 ± 18.4	0.0 ± 5.3	0.97
P value	0.12	0.25	0.23
Ht, %
Group A	41.7 ± 3.8	44.0 ± 4.3	2.6 ± 2.3	<0.001
Group B	43.5 ± 4.1	45.4 ± 4.4	1.7 ± 2.4	<0.001
P value	0.07	0.24	0.15
HbA1c, %
Group A	7.4 ± 0.9	7.1 ± 0.7	−0.2 ± 0.4	0.004
Group B	7.2 ± 0.8	7.0 ± 0.7	−0.2 ± 0.6	0.09
P value	0.46	0.69	0.98
Blood glucose, mg/dL
Group A	137.1 ± 40.6	122.7 ± 22.8	−18.0 ± 34.7	0.018
Group B	147.8 ± 39.9	139.8 ± 41.5	−8.4 ± 49.4	0.51
P value	0.38	0.07	0.47
β‐hydroxybutyric acid, μmol/L
Group A	3.97 ± 0.96	4.28 ± 0.96	0.31 ± 0.83	0.045
Group B	3.98 ± 0.81	4.28 ± 0.92	0.29 ± 1.05	0.15
P value	0.95	1.00	0.94

Data are expressed as mean ± SD. Summary statistics of measurements and changes for each observation point were calculated for each group, and two‐sample t‐tests were performed for measurements for between‐group comparisons. One‐sample t‐tests for comparison within groups and two‐sample t‐tests for comparison between groups were performed for the amount of change. Group A, group receiving tofogliflozin without salt restriction; Group B, group receiving tofogliflozin with dietary sodium restriction.

HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; TG, triglycerides; UA, uric acid.

There were no significant group differences in the change in the home blood pressure or body composition (Table 4). Group B showed a significant increase in skeletal muscle mass to total body weight ratio and a significant decrease in the nocturnal home systolic blood pressure. There were no significant differences in the summary statistics of the QOL questionnaires between or within groups (Table S1).

Table 4.

Change in the results of home blood pressure and body composition before and after taking tofogliflozin

Total	Before	After	Change by intervention	P value
Home systolic blood pressure at night, mmHg
Group A	122.8 ± 9.5	120.0 ± 14.8	−1.6 ± 13.6	0.72
Group B	122.7 ± 19.2	110.3 ± 10.0	−6.4 ± 8.0	0.043
P value	0.99	0.10	0.36
Home diastolic blood pressure at night, mmHg
Group A	68.1 ± 7.1	68.3 ± 10.6	0.4 ± 6.3	0.83
Group B	74.5 ± 15.1	65.7 ± 7.8	−4.5 ± 7.1	0.09
P value	0.24	0.54	0.13
Skeletal muscle mass to total body weight ratio
Group A	0.377 ± 0.045	0.372 ± 0.042	−0.002 ± 0.021	0.67
Group B	0.377 ± 0.040	0.386 ± 0.038	0.008 ± 0.019	0.043
P value	0.94	0.22	0.08

Data are expressed as mean ± SD. Summary statistics of measurements and changes for each observation point were calculated for each group, and two‐sample t‐tests were performed for measurements for between‐group comparisons. One‐sample t‐tests for comparison within groups and two‐sample t‐tests for comparison between groups were performed for the amount of change. Group A, group receiving tofogliflozin without salt restriction; Group B, group receiving tofogliflozin with dietary sodium restriction.

Safety evaluation items

The adverse events reported as disease are shown in Table 5. There were no significant differences in adverse events between groups. Only one serious adverse event was reported in each group, none of which were related to the study drug, and the outcome was recovery.

Table 5.

Deaths and adverse events

Adverse event	Group A	Group B	P value
N	34	31
Death	0 (0.0)	0 (0.0)	–
Adverse events	4 (11.8)	4 (12.9)	1.00
COVID‐19 infection	1 (2.9)	1 (3.2)	1.00
Depression	0 (0.0)	1 (3.2)	0.48
Erosive balanitis	1 (2.9)	0 (0.0)	1.00
Nausea	1 (2.9)	0 (0.0)	1.00
Acute myocardial infarction	0 (0.0)	1 (3.2)	0.48
Hemorrhagic shock	1 (2.9)	0 (0.0)	1.00
Abdominal discomfort	0 (0.0)	1 (3.2)	0.48
Severe adverse events
Severe acute myocardial infarction	0 (0.0)	1 (3.2)	0.48
Severe hemorrhagic shock	1 (2.9)	0 (0.0)	1.00

Data are expressed as number (%) and were compared by Fisher's exact test. Group A, group receiving tofogliflozin without salt restriction; Group B, group receiving tofogliflozin with dietary sodium restriction.

DISCUSSION

The primary endpoint of this study was the frequency of nocturia in patients with type 2 diabetes who had nocturia at 12 weeks after tofogliflozin administration. However, there was no increase in the frequency of nocturia, which is generally considered a major adverse event with SGLT2i, with or without salt restriction.

As expected for SGLT2i ²⁹ , urinary glucose excretion increased significantly in both groups after tofogliflozin administration, indicating the effect of SGLT2i on glucose elimination and an increase in urine volume during the day due to osmotic diuresis ³⁰ , ³¹ . It is known that furosemide administration in the afternoon improves nocturia, resulting in excretion of water accumulated in the body as urine and a time shift in urination time ³² . These results indicate the short half‐life of tofogliflozin ³³ . The fact that there was no increase in nocturnal urinary frequency after tofogliflozin administration may offer great encouragement to patients with type 2 diabetes who often experience nocturnal urination.

It should be noted that the number of nocturnal urinations (P = 0.049) significantly decreased in group B, and a decreasing trend was also observed in urine volume (P = 0.07) during the night. Urinary sodium excretion also decreased significantly in group B compared with group A, indicating that the salt restriction instruction was successful. The reason for the improvement in nocturnal urinary frequency in group B compared with group A is thought to be that the effect of salt restriction and the short half‐life of tofogliflozin shifted the urine excretion time of glucose and sodium to daytime, and instead of increasing the amount and frequency of urination during the day, the amount and frequency of urination decreased relatively at night ²¹ , ³⁴ . This effect was more evident in the combined salt restriction group than in group A because of the avoidance of sodium retention in the body. Moreover, the nocturnal home blood pressure improved in group B, indicating that salt restriction is effective in treating non‐dipper type hypertension. Previous reports have also shown that increased salt intake is associated with an increase in urine volume due to osmotic diuresis 4 h after salt intake ³⁴ , ³⁵ .

Although SGLT2i promote glucose and sodium excretion downstream in the tubules ³⁶ , urinary sodium excretion is only altered in the short term and returns to baseline quickly because of a compensatory enhancement of the renin–angiotensin system ³⁷ . Therefore, the urinary time shift effect in relation to urinary sodium excretion was consistent with the effect of salt restriction.

As for changes in body composition, group B showed a significant increase in skeletal muscle mass to total body weight ratio. A previous report on Japanese subjects showed a decrease in skeletal muscle mass and body weight 12 weeks after the initiation of SGLT2i, and it has been shown that SGLT2i result in a uniform decrease in both intracellular and extracellular fluid volume, which also leads to weight loss. In the present study, there was no change in muscle mass in the salt‐restricted group; however, as noted above, the skeletal muscle mass to total body weight ratio increased because of the reduction in fluid volume.

Our study has some limitations. First, we investigated only Japanese individuals and did not evaluate racial differences. Second, there was no difference in the estimated salt intake between the two groups, which does not provide assurance about salt restriction interventions. Moreover, the frequency of nocturia before tofogliflozin administration was low in both groups; thus, the possibility that tofogliflozin had little effect on nocturia or had been underestimated cannot be ruled out. Finally, since we evaluated urinary frequency separated by wake and bedtime and could not investigate it in detail by the time of day, we were unable to definitively prove the effect of tofogliflozin on the urinary time shift. However, it should be noted that this study had several strengths. This well‐designed multicenter study is the first to examine the effects of tofogliflozin and salt restriction on nocturnal and diurnal urinary frequency and volume in patients with type 2 diabetes mellitus who have nocturia.

In conclusion, the effect of tofogliflozin, an SGLT2i with the shortest half‐life, on the frequency of nocturia in patients with type 2 diabetes was investigated, and it was found that the frequency of nocturia did not increase upon tofogliflozin administration. In particular, combining tofogliflozin administration with dietary salt restriction significantly reduced nocturia.

FUNDING

The authors disclosed receiving the following financial assistance for the study, authorship, and/or publication of this article; the TOP‐STAR study was funded by Kowa Corporation, including paper processing fees. The grant number is not applicable. No drugs were provided or funded by the sponsor. The granting organization had no involvement in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

DISCLOSURE

Nakajima H received personal fees from Nippon Boehringer Ingelheim Co., Ltd, Okada H received personal fees from Mochida Pharma Co., Ltd, Teijin Pharma Ltd, Kissei Pharmaceutical Co., Ltd, MSD K.K., Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., AstraZeneca K.K., Novo Nordisk Pharma Ltd, Daiichi Sankyo Co., Ltd, Kyowa Hakko Kirin Company Ltd, Takeda Pharmaceutical Co., Ltd, Kowa Pharmaceutical Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd, and Ono Pharmaceutical Co., Ltd, Hamaguchi M received grants from Kowa Pharma Co. Ltd, AstraZeneca K.K., Ono Pharma Co., Ltd, and received personal fees from Kowa Pharma Co., Ltd, Sumitomo Pharma Co., Eli Lilly, Japan, Ono Pharma Co., Ltd, Daiichi Sankyo Co., Ltd, AstraZeneca K.K., Mitsubishi Tanabe Pharma Corp., and Sanofi K.K. Fukui M received grants from Kowa Pharma Co., Ltd, Ono Pharma Co., Ltd, Mitsubishi Tanabe Pharma Corp., Oishi Kenko Inc., Yamada Bee Farm, Nippon Boehringer Ingelheim Co., Ltd, Abbott Japan Co., Ltd, Daiichi Sankyo Co., Ltd, Kyowa Kirin Co., Ltd, MSD K.K., Sumitomo Pharma Co., Ltd, TERUMO Co., Taisho Pharma Co., Novo Nordisk Pharma Ltd, Kissei Pharma Co., Ltd, Johnson & Johnson K.K., Sanofi K.K., Tejin Pharma Ltd, Sanwa Kagagu Kenkyusho Co., Ltd, Eli Lilly, Japan, K.K., Terumo Corp., Nippon Chemiphar Co., Ltd, Astellas Pharma Inc., Medical Co., and received personal fees from Kowa Pharma Co., Ltd, AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd, Kissei Pharma Co., Ltd, Mitsubishi Tanabe Pharma Corp., Novo Nordisk Pharma Ltd, Astellas Pharma Inc., Kyowa Kirin Co., Ltd, MSD K.K., Sumitomo Dainippon Pharma Co., Ltd, Sanofi K.K., TERUMO Co., Mochida Pharma Co., Ltd, Medtronic Japan Co., Ltd, Ono Pharma Co., Ltd, Sanwa Kagaku Kenkyusho Co., Ltd, Taisho Pharma Co., Ltd, Nipro Corp. Eli Lilly Japan K.K., Bayer Yakuhin, Ltd, Abbott Japan Co., Ltd, Teijin Pharma Ltd., Arkray Inc., and Daiichi Sankyo Co., Ltd. The remaining authors declare that they have no competing interests.

Approval of the research protocol: The research protocol was approved by the ethics committees of the Kyoto Prefectural University of Medicine (CRB5200001).

Informed consent: Written informed consent was obtained from all participants prior to their inclusion in this study.

Registry and the registration no. of the study/trial: This study was registered with the Japan Clinical Trial Registry (jRCTs051210212) on March 30, 2022.

Animal studies: N/A.

Supporting information

Appendix S1. Study Protocol for a TOP‐STAR Study

Table S1. Change in the results of questionnaire