ABSTRACT
Introduction
The renoprotective effects of luseogliflozin, a sodium‐glucose cotransporter 2 inhibitor, in patients with renal dysfunction are unexamined. We evaluated the efficacy of luseogliflozin in slowing renal function decline among patients with type 2 diabetes mellitus and moderate to severe renal dysfunction.
Materials and Methods
In a multicenter, randomized, open‐label, controlled clinical trial, patients with type 2 diabetes mellitus and an estimated glomerular filtration rate based on serum creatinine (eGFRcreat) of 15–45 mL/min/1.73 m2 were randomized into luseogliflozin or control groups. The primary endpoint was the change in eGFRcreat from baseline to 104 weeks. Secondary endpoints included eGFRcreat and eGFRcreat slope changes from 4 to 104 weeks (chronic eGFRcreat slope).
Results
Among 152 participants, eGFRcreat change from baseline to 104 weeks did not significantly differ between groups. The luseogliflozin group showed a significant decrease in eGFRcreat from 2 to 12 weeks compared to the control group; the largest decline occurred at 4 weeks (initial eGFR decline). There were no differences between groups thereafter. The chronic eGFRcreat slope was less negative in the luseogliflozin group compared to the control group (not significant). Conversely, subgroup analysis indicated that the difference in chronic eGFRcreat slope between groups was significantly greater (with a less negative or even positive slope observed in the luseogliflozin group compared to the control group) among patients with eGFRcreat <30 mL/min/1.73 m2, urinary albumin/creatinine ratio <30 mg/g creatinine, systolic blood pressure <130 mmHg, or females.
Conclusions
Although the primary endpoint did not reach statistical significance, luseogliflozin may provide renoprotective benefits in patients with type 2 diabetes mellitus and moderate‐to‐severe renal impairment, potentially by slowing eGFRcreat decline post‐initial decline.
Keywords: Diabetes mellitus, Diabetic kidney disease, Glomerular filtration rate
Luseogliflozin alleviated renal function decline (eGFR) after an initial decrease, showing renoprotective effects in patients with renal impairment. Luseogliflozin did not increase renal events, showing safety even in patients with moderate‐to‐severe renal impairment.
INTRODUCTION
Diabetic nephropathy occurs in 20–40% of patients with diabetes mellitus (DM) 1 . Diabetic kidney disease (DKD) encompasses typical diabetic nephropathy and atypical diabetes‐related kidney disease, the latter of which is associated with glomerular filtration rate (GFR) decline without overt albuminuria 2 . DKD is the leading cause of end‐stage renal disease (ESRD) 3 , and patients with DKD are at a high risk of cardiovascular disease (CVD) 4 .
GFR measurements are essential for diagnosing and staging chronic kidney diseases (CKD), including DKD 5 . The GFR is typically expressed as the estimated GFR (eGFR) based on serum creatinine (Cre) levels. Assessing the magnitude of change in GFR through long‐term observation is necessary to evaluate the effectiveness of treatments aimed at slowing GFR decline. Additionally, assessing the rate of decline, or GFR slope, over a specific timeframe is crucial for predicting future changes in renal function 6 , 7 . Previous reports have shown that steeper negative GFR slopes are associated with an increased risk of ESRD, CVD, and all‐cause mortality 8 , 9 .
Large placebo‐controlled trials have demonstrated that sodium‐glucose cotransporter 2 inhibitors (SGLT2is) offer significant benefits in reducing the risk of cardiorenal disease progression, including atherosclerotic disease, heart failure, and CKD, in patients with type 2 diabetes mellitus. Notably, the CREDENCE trial 10 , which targeted patients with diabetic nephropathy, along with the DAPA‐CKD 11 , 12 , and EMPA‐KIDNEY 13 , 14 , 15 , 16 trials, which targeted patients with CKD with or without type 2 diabetes mellitus, demonstrated that canagliflozin, dapagliflozin, and empagliflozin significantly reduced the risk of renal composite outcomes and improved the GFR slope compared to placebo, independent of glucose control. Therefore, SGLT2is have been recommended for patients with eGFR ≥20 mL/min/1.73 m2 who have type 2 diabetes mellitus with CKD 17 , and the renoprotective benefits of these medications are considered a class effect. However, the renoprotective effects of SGLT2is in patients with severe renal dysfunction, including an eGFR of 15–20 mL/min/1.73 m2, have not been examined. Among SGLT2is, luseogliflozin exhibits similar pharmacokinetics across patients with varying levels of renal function, including those with moderate‐to‐severe renal impairment 18 . Consequently, it may be unnecessary to consider dose reductions or an increased risk of adverse events due to heightened drug exposure, regardless of the degree of renal dysfunction. Nevertheless, the efficacy and safety of luseogliflozin in slowing renal function decline in patients with type 2 diabetes mellitus and CKD, particularly those with moderate‐to‐severe renal dysfunction, have not been adequately investigated.
MATERIALS AND METHODS
Study design
The Renal Efficacy Study of LUseogliflozin in patients with Type 2 diabetes mellitus and impaired renal function (RESOLUTION study) was a multicenter, open‐label, randomized‐controlled trial conducted across 22 medical institutions (Table S1) in Japan. Participants were enrolled between August 2020 and September 2022. All study procedures were conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act, and other current legal regulations in Japan. The Kanazawa Medical University Clinical Research Review Board approved the study protocol (approval number: T013; July 17, 2020). This study was registered with the Japan Registry of Clinical Trials (jRCT) (registration number: jRCTs041200039). Written informed consent was obtained from all enrolled individuals meeting the eligibility criteria before the intervention. Data collection, management, monitoring, audits, and statistical analyses were outsourced to third‐party entities (Soiken Inc., Osaka, Japan; EviPRO Co., Ltd., Tokyo, Japan) to avoid bias and ensure quality.
Subjects
The main inclusion criteria were as follows: (1) type 2 diabetes mellitus diagnosis, (2) a GFR estimated by serum creatinine (eGFRcreat) of 15–45 mL/min/1.73 m2 at the latest visit (within 12 weeks) before providing consent, and (3) aged ≥20 years at the time of providing consent. Full inclusion and exclusion criteria are listed in Table S2.
Randomization, study intervention, and observation
Eligible patients who provided consent were randomly assigned to the luseogliflozin or control groups at an approximate 1:1 ratio using a minimization procedure to balance allocation factors (age < 70 or ≥70 years; eGFRcreat <30 or ≥30 mL/min/1.73 m2; and urinary albumin creatinine ratio (UACR) <300 or ≥300 mg/g·Cre). Patients in the luseogliflozin group received luseogliflozin at an initial dose of 2.5 mg daily. If glycemic control was insufficient, a dose increase to 5.0 mg daily was permitted with careful follow‐up. Patients assigned to the control group did not receive luseogliflozin but continued their current treatment at the time of consent. All patients were subsequently observed for 104 weeks. The detailed observation schedules/items and intervention provisions, including prohibited/restricted agents and rescue therapy, are presented in Tables S3 and S4, respectively.
Outcomes
The primary endpoint was the change in eGFRcreat from baseline to week 104. Secondary endpoints included change in eGFRcreat from weeks 4 to 104, similar outcomes using GFR estimated by serum cystatin C (eGFRcys), other renal, hepatic, and metabolic biomarkers, and frequency of adverse events. Prespecified exploratory endpoints included eGFR slopes 19 between baseline and week 104 (total slope) and weeks 4 and 104 (chronic slope), and their subgroup analyses. The comprehensive list of outcomes is shown in Table S5.
Sample size
The eGFR slope in patients with stage G3b or G4 CKD was −2.6 ± 10 mL/min/1.73 m2/year in the Chronic Kidney Disease‐Japan Cohort (CKD‐JAC) 20 , whereas that after luseogliflozin initiation in patients with similar CKD stages was −0.2 mL/min/1.73 m2/year based on the stratified analysis of clinical trials 21 and postmarketing surveillance 22 . Therefore, we assumed that the changes in eGFRcreat from baseline to week 104 would be −5.2 ± 10 mL/min/1.73 m2 and −0.4 mL/min/1.73 m2 in the control and luseogliflozin groups, respectively. Consequently, the minimum sample size required to achieve a significance level of 0.05 from a two‐sided test with a statistical power of 85% was determined to be 79 cases per group (158 cases for two groups). We estimated the dropout rate to be 20%; hence, the planned number of participants was set to 100 cases per group (200 cases per group).
Statistical analysis
All tests were two‐sided, and statistical significance was set at P‐value <0.05. Multiplicity was not adjusted for any of the endpoints. A statistical analysis plan was developed before the database lock. All statistical analyses were outsourced to third‐party entities (EviPRO Co., Ltd.) to avoid bias and ensure quality. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).
Three analysis sets were defined in this study. The full analysis set (FAS) included all patients registered and assigned to either of the study treatment groups. Patients with severe protocol violations were excluded from the FAS. The per‐protocol set (PPS) excluded patients with a protocol violation. The safety analysis set included all registered patients who received at least one dose of the study intervention. Primary endpoint analyses were performed using data from the FAS and PPS, whereas secondary endpoint analyses were performed using FAS data. A safety analysis was performed using the safety analysis set.
Patient characteristics at baseline were reported as frequencies and proportions for categorical data and as summary statistics (number of patients, mean, standard deviation, minimum, first quartile, median, third quartile, and maximum) for continuous data.
The primary endpoint, change eGFRcreat from baseline to week 104, was analyzed through analysis of covariance, with the allocation factors as covariates. Summary statistics for the measurements and changes at each time point were calculated, and one‐ and two‐sample t‐tests were performed for within‐group and between‐group comparisons, respectively.
Summary statistics (number of patients and proportion) were calculated for secondary endpoints involving proportions, and the chi‐squared test and Fisher's exact test were performed for between‐group comparisons. Summary statistics for measurements and changes at each time point were calculated for secondary endpoints involving continuous variables, and one‐ and two‐sample t‐tests were performed for within‐group and between‐group comparisons, respectively. Wilcoxon signed‐rank tests for within‐group changes and rank‐sum tests for between‐group comparisons were performed if the values deviated from the normal distribution.
Regarding exploratory endpoints, the eGFR slope was calculated according to the CANPIONE study 19 . Briefly, the eGFR slope was estimated using a piecewise linear mixed‐effects model (with knots at week 4), assuming that data were missing at random. Two phases of eGFR slopes (total [weeks 0–104] and chronic [weeks 4–104]) were estimated for each group, along with differences in the slope between the groups at each phase, changes in eGFR slopes, and their 95% confidence intervals (CIs). The model utilized an unstructured covariance structure, with patients as random effects and treatment group, time, interaction between the treatment group and time, and allocation factors as fixed effects. Compound symmetry was used if the results did not converge.
RESULTS
Baseline participant characteristics
The study population flowchart is shown in Figure 1. In total, 3,010 patients were evaluated for eligibility, and 152 were enrolled and randomized into the luseogliflozin (76 patients) or control group (76 patients). One patient in the luseogliflozin group was excluded due to dropout before the initiation of the study intervention, resulting in a safety analysis set constituting 75 and 76 patients in the luseogliflozin and control groups, respectively. After the initiation of the study intervention, one patient in the luseogliflozin group was excluded owing to a prohibited agent violation, and five in the control group were excluded owing to a prohibited agent violation (four patients) and dropout on the initiation day of the study intervention, resulting in a FAS constituting 74 and 71 patients in the luseogliflozin and control groups, respectively. Twenty‐four and 14 patients were excluded from the PPS in the luseogliflozin and control groups, respectively, resulting in a PPS constituting 50 and 57 patients, respectively.
Figure 1.
Study flowchart of patient enrolment and analysis.
Baseline patient characteristics are presented in Table 1. The baseline characteristics were well balanced between the groups, except for systolic blood pressure (SBP) (P = 0.004), hepatic disease comorbidities (P = 0.034), and diabetic retinopathy (P = 0.045). Baseline medication use, including the use of antidiabetic and antihypertensive agents, showed no between‐group differences.
Table 1.
Demographic and clinical characteristics of the patients at baseline
| Characteristics | Luseogliflozin group (n = 74) | Control group (n = 71) | Total (n = 145) |
|---|---|---|---|
| Age (year) | 71.4 ± 9.1 | 71.8 ± 7.8 | 71.6 ± 8.5 |
| Sex | |||
| Male | 49 (66.2) | 49 (69.0) | 98 (67.6) |
| Female | 25 (33.8) | 22 (31.0) | 47 (32.4) |
| Height (cm) | 161.6 ± 8.6 | 161.5 ± 10.1 | 161.5 ± 9.3 |
| Weight (kg) | 66.7 ± 12.2 | 66.1 ± 13.0 | 66.4 ± 12.6 |
| BMI (kg/m2) | 25.5 ± 4.1 | 25.3 ± 4.1 | 25.4 ± 4.1 |
| Duration of diabetes (years) | 17.7 ± 10.9 (67) | 19.0 ± 11.3 (62) | 18.3 ± 11.1 (129) |
| HbA1c (%) | 7.3 ± 1.1 | 7.1 ± 0.9 | 7.2 ± 1.0 |
| UACR (mg/g·Cre) | |||
| UACR <30 mg/g·Cre | 13 (17.8)/73 | 13 (18.8)/69 | 26 (18.3)/142 |
| 30 ≤ UACR <300 mg/g·Cre | 26 (35.6)/73 | 31 (44.9)/69 | 57 (40.1)/142 |
| 300 mg/g·Cre ≤ UACR | 34 (46.6)/73 | 25 (36.2)/69 | 59 (41.5)/142 |
| eGFRcreat (mL/min/1.73 m2) | |||
| eGFRcreat <15 mL/min/1.73 m2 | 1 (1.4) | 0 (0.0) | 1 (0.7) |
| 15 ≤ eGFRcreat < 30 mL/min/1.73 m2 | 12 (16.2) | 15 (21.1) | 27 (18.6) |
| 30 ≤ eGFRcreat < 45 mL/min/1.73 m2 | 49 (66.2) | 44 (62.0) | 93 (64.1) |
| 45 mL/min/1.73 m2 ≤ eGFRcreat | 12 (16.2) | 12 (16.9) | 24 (16.6) |
| Blood pressure | |||
| Systolic blood pressure (mmHg) | 138.1 ± 15.7 | 130.4 ± 15.8 | 134.4 ± 16.2 |
| Diastolic blood pressure (mmHg) | 74.1 ± 11.1 | 71.8 ± 12.7 | 73.0 ± 11.9 |
| History | |||
| Cardiocerebrovascular disease | 17 (23.0) | 17 (23.9) | 34 (23.4) |
| Comorbidity | |||
| Macrovascular disease | 22 (29.7) | 17 (23.9) | 39 (26.9) |
| Cerebrovascular disease | 5 (6.8) | 5 (7.0) | 10 (6.9) |
| Coronary artery disease | 16 (21.6) | 10 (14.1) | 26 (17.9) |
| Peripheral artery disease | 4 (5.4) | 5 (7.0) | 9 (6.2) |
| Microvascular disease | 66 (89.2) | 62 (87.3) | 128 (88.3) |
| Diabetic nephropathy | |||
| Stage 2 | 21 (28.4) | 27 (38.0) | 48 (33.1) |
| Stage 3 | 26 (35.1) | 16 (22.5) | 42 (29.0) |
| Stage 4 | 15 (20.3) | 15 (21.1) | 30 (20.7) |
| Diabetic retinopathy | |||
| Simple diabetic retinopathy | 18 (24.3) | 13 (18.6)/70 | 31 (21.5)/144 |
| Preproliferative diabetic retinopathy | 5 (6.8) | 10 (14.3)/70 | 15 (10.4)/144 |
| Proliferative diabetic retinopathy | 12 (16.2) | 3 (4.3)/70 | 15 (10.4)/144 |
| Diabetic neuropathy | 21 (28.4) | 20 (28.2) | 41 (28.3) |
| Hepatic disease | 9 (12.2) | 2 (2.8) | 11 (7.6) |
| Hypertension | 68 (91.9) | 68 (95.8) | 136 (93.8) |
| Dyslipidemia | 61 (82.4) | 56 (78.9) | 117 (80.7) |
| Concomitant medication use | |||
| Anti‐diabetic agent | 70 (94.6) | 67 (94.4) | 137 (94.5) |
| Sulfonylurea | 9 (12.2) | 7 (9.9) | 16 (11.0) |
| Alpha‐glucosidase inhibitor | 13 (17.6) | 11 (15.5) | 24 (16.6) |
| Biguanide | 18 (24.3) | 18 (25.4) | 36 (24.8) |
| Glinide | 16 (21.6) | 17 (23.9) | 33 (22.8) |
| Thiazolidine | 3 (4.1) | 4 (5.6) | 7 (4.8) |
| Dipeptidyl‐peptidase 4 inhibitor | 44 (59.5) | 42 (59.2) | 86 (59.3) |
| Oral GLP‐1 receptor agonist | 2 (2.7) | 1 (1.4) | 3 (2.1) |
| Human GLP‐1 analog injectable | 2 (2.7) | 6 (8.5) | 8 (5.5) |
| Long‐acting GLP‐1 receptor agonist | 7 (9.5) | 11 (15.5) | 18 (12.4) |
| Insulin | 22 (29.7) | 20 (28.2) | 42 (29.0) |
| Others | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Antihypertensive | 66 (89.2) | 60 (84.5) | 126 (86.9) |
| Diuretic | 12 (16.2) | 6 (8.5) | 18 (12.4) |
| Potassium‐sparing diuretic | 5 (6.8) | 4 (5.6) | 9 (6.2) |
| Calcium antagonist | 52 (70.3) | 41 (57.7) | 93 (64.1) |
| Angiotensin receptor antagonist | 51 (68.9) | 47 (66.2) | 98 (67.6) |
| Angiotensin‐converting enzyme inhibitor | 1 (1.4) | 3 (4.2) | 4 (2.8) |
| Alpha1 antagonist | 3 (4.1) | 2 (2.8) | 5 (3.4) |
| Alpha/beta‐antagonist | 6 (8.1) | 2 (2.8) | 8 (5.5) |
| Beta‐antagonist | 7 (9.5) | 7 (9.9) | 14 (9.7) |
| Transdermal beta1 antagonist | 0 (0.0) | 1 (1.4) | 1 (0.7) |
| Direct renin inhibitor | 1 (1.4) | 0 (0.0) | 1 (0.7) |
| Angiotensin receptor neprilysin inhibitor | 1 (1.4) | 0 (0.0) | 1 (0.7) |
| Loop diuretic | 0 (0.0) | 3 (4.2) | 3 (2.1) |
| Long‐acting loop diuretic | 2 (2.7) | 1 (1.4) | 3 (2.1) |
| Nonthiazide antihypertensive | 1 (1.4) | 1 (1.4) | 2 (1.4) |
| Mineralocorticoid receptor antagonist | 3 (4.1) | 2 (2.8) | 5 (3.4) |
| Others | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Dyslipidemia therapeutic agent | 53 (71.6) | 51 (71.8) | 104 (71.7) |
| Vitamin D | 4 (5.4) | 0 (0.0) | 4 (2.8) |
Data are presented as the mean ± SD for continuous variables and as the number of patients (%) for categorical variables. In cases where the number of patients with data differed from the number of patients in each group, the number of patients with data is shown after the data in parentheses. BMI, body mass index; eGFR, glomerular filtration rate estimated using serum creatinine; GLP‐1, glucagon‐like peptide 1; UACR, urinary albumin/creatinine ratio.
Changes in eGFR and eGFR slope
The primary endpoint was the change in eGFRcreat from baseline to 104 weeks. eGFRcreat significantly decreased from baseline to 104 weeks in both the luseogliflozin and control groups, and there was no significant difference in the change between the groups (Figure 2a). At other observation points, eGFRcreat significantly decreased in the luseogliflozin group throughout the observation period, with the largest decline occurring at 4 weeks (initial eGFR decline). In contrast, the control group exhibited a significant decrease from baseline at weeks 38, 52, 76, and 88. Notably, the luseogliflozin group showed a significant decrease in eGFRcreat compared to the control group during weeks 2–12.
Figure 2.
Change in eGFRcreat and eGFRcreat slope. Data are presented as mean ± standard error. One‐sample t‐tests were used for within‐group comparisons. Two‐sample t‐tests were used for between‐group comparisons. †Represents P < 0.05 for the within‐group comparison. eGFRcreat, glomerular filtration rate estimated by serum creatinine. *P < 0.05, between‐group comparison of changes. The eGFRcreat slope was estimated using a piecewise linear mixed‐effects model (with knots at week 4), assuming that data were missing at random. It was performed with an unstructured covariance structure, with patients as random effects and treatment group, time, interaction between the treatment group and time, and allocation factors as fixed effects. Compound symmetry was used if the results did not converge.
The change in eGFRcreat from week 4 was analyzed as a prespecified secondary endpoint, with a significant decrease in eGFRcreat from week 4 to weeks 38, 52, 76, 88, and 104 in the control group. In contrast, no significant changes were observed in the luseogliflozin group during the observation period. Consequently, the control group exhibited a significant decrease in eGFRcreat compared to the luseogliflozin group at weeks 38 and 76 (Figure 2b).
The total eGFRcreat slope was numerically less negative in the luseogliflozin group than in the control group, without statistical significance (P = 0.69; Figure 2a). Additionally, the chronic eGFRcreat slope was numerically less negative in the luseogliflozin group than in the control group, without statistical significance (P = 0.22; Figure 2b).
Sensitivity analyses of eGFRcreat using PPS and eGFRcys using FAS showed similar tendencies (Figures S1 and S2).
In a prespecified exploratory subgroup analysis, the adjusted between‐group difference in the chronic eGFRcreat slope was significantly greater, showing a less negative or even positive slope, in the luseogliflozin group compared to the control group, among patients with the baseline levels of eGFRcreat <30 mL/min/1.73 m2, UACR <30 mg/g·Cre, SBP <130 mmHg, or females (Figure 3).
Figure 3.
Subgroup analysis of eGFRcreat slope. Data are presented as the adjusted mean ± standard error or adjusted between‐group difference (95% confidence interval). The eGFRcreat slope was estimated using a piecewise linear mixed‐effects model (with knots at week 4), assuming that data were missing at random. It was performed with an unstructured covariance structure, with patients as random effects and treatment group, time, interaction between the treatment group and time, and allocation factors as fixed effects. Compound symmetry was used if the results did not converge. eGFRcreat, glomerular filtration rate estimated by serum creatinine.
The proportion of patients whose eGFRcreat decreased by ≥30% from baseline did not differ between the groups throughout the observation period (Figure S3A). The proportion of patients whose eGFRcreat decreased by ≥20% from baseline was significantly larger in the luseogliflozin group (eight patients [11.3%]) than in the control group (one patient [1.4%]; P = 0.033) only at week 4, with no significant between‐group differences at other observation points (Figure S3B). The proportion of patients whose eGFRcreat was <10 mL/min/1.73 m2 (Figure S3C) and the incidence of dialysis (Figure S3D) did not show significant between‐group differences throughout the observation period.
Changes in UACR
UACR significantly decreased from baseline to weeks 26 and 52 in the luseogliflozin group, showing a significant decrease in the luseogliflozin group compared to the control group at weeks 52 (P = 0.016) and 64 (P = 0.049; Figure S4).
Changes in clinical laboratory tests and BMI
HbA1c levels in the luseogliflozin group significantly decreased from baseline to weeks 8 and 12. However, no significant between‐group differences were observed throughout the observation period (Figure 4a). Body mass index (BMI) in the luseogliflozin group significantly decreased from baseline throughout the observation period and was significantly lower than that in the control group (Figure 4b). SBP (at weeks 4, 8, 12, 26, and 104), diastolic blood pressure (at weeks 12 and 76), aspartate aminotransferase (at weeks 64 and 76), gamma‐glutamyl transpeptidase (γGTP) (at weeks 8 and 76), and uric acid (at weeks 38 and 88) significantly decreased in the luseogliflozin group compared to the control group (Figure 4c–h).
Figure 4.
Change in laboratory test values. Data are presented as mean ± standard error. One‐sample t‐tests were used for within‐group comparisons. Two‐sample t‐tests were used for between‐group comparisons. †Represents P < 0.05 for the within‐group comparison. *P < 0.05, between‐group comparison of changes. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DBP, diastolic blood pressure; HbA1c, hemoglobin A1c; SBP, systolic blood pressure; γ‐GTP, gamma‐glutamyl transpeptidase.
The percent change from baseline significantly increased for total ketone bodies (at weeks 52 and 104), 3‐hydroxybutyric acid (3OHBA) (at weeks 52 and 104), and acetoacetic acid (AcAc) (at week 52) in the luseogliflozin group. However, no significant differences were observed between the groups (Figure S5A–C). A post‐hoc analysis demonstrated a significant positive correlation between the chronic eGFRcreat slope and the percent change from baseline to week 104 in total ketone bodies (correlation coefficient (95% CI): 0.27 (0.02, 0.49), P = 0.035) and 3OHBA (0.27 (0.02, 0.49), P = 0.036) in the luseogliflozin group. AcAc did not show a significant correlation with the chronic eGFRcreat slope (correlation coefficient (95% CI): 0.23 (−0.03, 0.45), P = 0.08; Table S6).
Safety
During the study period, two patients (2.7%) died in the luseogliflozin group (one due to disseminated intravascular coagulation after percutaneous coronary intervention for myocardial infarction and another due to alcoholic cirrhosis), and one (1.3%) died in the control group (due to myocardial infarction; Table S7). However, none of these deaths were judged to have been caused by the intervention. Adverse events occurred in 54 patients (72.0%) in the luseogliflozin group and 54 (71.1%) in the control group, whereas serious adverse events occurred in 22 patients (29.3%) in the luseogliflozin group and 21 (27.6%) in the control group. Frequent adverse events were hypertension (11 [14.7%] and 13 [17.1%] patients in the luseogliflozin and control groups, respectively), edema (7 [9.3%] and 4 [5.3%] patients, respectively), and hyperglycemia (7 [9.3%] and 9 [11.8%] patients, respectively), with no difference in the frequency of adverse events between groups.
DISCUSSION
This is the first study to investigate whether luseogliflozin has an effect on the preservation of renal function in patients with type 2 diabetes mellitus and moderate‐to‐severe renal dysfunction. The change in eGFRcreat from baseline to 104 weeks, as the primary endpoint, did not significantly differ between the groups. In the luseogliflozin group, an initial decline in eGFR was observed, with the largest decrease occurring 4 weeks following the intervention. However, the subsequent chronic eGFR slope was less negative than that of the control group, although this difference was not statistically significant.
The results of three large randomized controlled trials: CREDENCE 10 , DAPA‐CKD 11 , and EMPA‐KIDNEY trials 13 , clearly demonstrated that SGLT2is provide significant benefits for renal composite outcomes. This served as the primary endpoint compared to placebo in patients with DKD or CKD, regardless of the presence of type 2 diabetes mellitus. Regarding renal function decline progression, the eGFR slope after the initial eGFR decline was less negative in the SGLT2i group compared to the placebo group in the three trials (−1.85 ± 0.13 vs −4.59 ± 0.14 mL/min/1.73 m2/year in CREDENCE 10 ; −1.67 ± 0.11 vs −3.59 ± 0.11 mL/min/1.73 m2/year in DAPA‐CKD 11 ; and −1.37 ± 0.08 vs −2.75 ± 0.08 mL/min/1.73 m2/year in EMPA‐KIDNEY 13 ), indicating long‐term preservation of renal function. In the present study, involving patients with type 2 diabetes mellitus and moderate‐to‐severe renal dysfunction, the trend was consistent with the results of the aforementioned trials. The chronic eGFRcreat slope after the initial decline was numerically less negative in the luseogliflozin group compared to the control group (−0.89 ± 0.39 vs −1.56 ± 0.39 mL/min/1.73 m2/year, respectively), although this difference was not statistically significant. A possible reason for the lack of statistically significant between‐group differences in the chronic eGFRcreat slope or the mean change in eGFRcreat from weeks 4–104 might be that the rate of eGFRcreat decline in the control group was lower than that observed in the three trials 10 , 11 , 13 . On the other hand, a previous systematic review indicated that the normal decline rate in healthy adults without hypertension ranges from −0.37 to −1.07 mL/min/1.73 m2/year 23 . While comparing data before and after the intervention was not possible, the chronic eGFRcreat slope after luseogliflozin intervention was nearly equivalent to that in healthy adults without hypertension. This suggests that luseogliflozin may have a renoprotective effect; however, further long‐term studies are necessary to evaluate its impact on the preservation of renal function.
In the three aforementioned trials, the benefit of SGLT2is on eGFR slope alleviation was demonstrated across the range of eGFR 13 , 24 , 25 , albuminuria 13 , 24 , SBP 24 , and sex 24 . Notably, in the EMPA‐KIDNEY 13 trial, it was observed that the higher the baseline UACR or eGFR value, the more pronounced the effect of empagliflozin in improving chronic eGFR slope. In the present study, stratified analysis showed that the chronic eGFRcreat slope in the luseogliflozin group was significantly less negative, or even positive, compared to the control group in patients with baseline eGFRcreat <30 mL/min/1.73 m2 or UACR <30 mg/g·Cre. Conversely, in patients with baseline eGFRcreat ≥30 mL/min/1.73 m2 or UACR ≥30 mg/g·Cre, luseogliflozin did not demonstrate a significant improvement in the chronic eGFRcreat slope. The discrepancies in these findings from the stratified analyses of eGFRcreat slopes may be attributed to the differences in chronic eGFR slopes observed in the control groups of these studies. Regarding the population with UACR ≥30 mg/g·Cre, the chronic eGFR slope in the control group was −1.69 ± 0.14 and −4.11 ± 0.11 mL/min/1.73 m2/year in patients with 30 ≤ UACR ≤300 mg/g·Cre and UACR >300 mg/g·Cre, respectively, and regarding the population with eGFR ≥30 mL/min/1.73 m2, it was −2.50 ± 0.12 mL/min/1.73 m2/year in patients with 30 ≤ eGFR <45 mL/min/1.73 m2 in the EMPA‐KIDNEY trial. In contrast, this study demonstrated chronic eGFRcreat slopes of −1.54 ± 0.48 and −0.82 ± 0.40 mL/min/1.73 m2/year in patients with UACR ≥30 mg/g·Cre and eGFRcreat ≥30 mL/min/1.73 m2, respectively. Thus, the lesser decline in eGFR in the control group of this study compared to that of the EMPA‐KIDNEY trial may have contributed to the smaller difference between the groups. On the other hand, the chronic eGFR slope in the control group was −0.89 ± 0.16 mL/min/1.73 m2/year in patients with UACR <30 mg/g·Cre, and −2.50 ± 0.12 mL/min/1.73 m2/year in patients with eGFR <30 mL/min/1.73 m2 in the EMPA‐KIDNEY trial. In contrast, this study showed chronic eGFRcreat slopes of −1.54 ± 0.55 and −3.87 ± 0.37 mL/min/1.73 m2/year for patients with UACR <30 mg/g·Cre and eGFRcreat <30 mL/min/1.73 m2, respectively. Thus, the more substantial decline in eGFR observed in the control group of this study compared to that of the EMPA‐KIDNEY trial may have resulted in a significant difference between the groups. In addition, the subgroups with baseline levels of SBP <130 mmHg or females showed that the chronic eGFRcreat slope was significantly less negative or even positive in the luseogliflozin group compared to the control group. However, the reason for the discrepancy in findings between this study and the three previously mentioned trials remains unclear.
Recent cohort studies conducted in several countries, including the United States 26 and Japan 27 , revealed a decrease in albuminuria prevalence owing to advancements in diabetes treatment among patients with DKD. Conversely, the prevalence of reduced GFR has increased over the past 20 years. Additionally, the aging population of patients with diabetes contributes to renal function decline. In this study, the mean age of participants was 71 years, and the stratified analysis indicated that luseogliflozin significantly improved the eGFRcreat slope compared to current treatments in the groups with eGFRcreat <30 mL/min/1.73 m2 or UACR <30 mg/g·Cre. Furthermore, luseogliflozin did not increase further renal function decline to eGFRcreat <10 mL/min/1.73 m2. These findings may be meaningful for the treatment of elderly patients with DKD who experience severe renal function decline without albuminuria, a trend that has been increasingly observed in clinical practice in recent years.
No significant difference was observed in the change in HbA1c levels between the two groups, which may be attributed to the open‐label nature of the trial. Specifically, some patients in the luseogliflozin group reduced the dose of other antidiabetic agents including insulin at the start of treatment to avoid hypoglycemia or excessive hypoglycemia. Additionally, the efficacy of luseogliflozin in reducing glucose levels may diminish based on the degree of renal impairment, particularly regarding its pharmacodynamic profile 18 , as well as other SGLT2is. In contrast, BMI significantly decreased during the observational period. Furthermore, other metabolic parameters such as SBP, hepatic and biliary enzymes, and serum uric acid values tended to decrease in the luseogliflozin group, similar to previous reports 28 , 29 , 30 , 31 . Serum ketone bodies significantly increased from baseline to weeks 52 and 104 in the luseogliflozin group in the within‐group comparison. Interestingly, a post‐hoc analysis demonstrated a significant positive correlation between the chronic eGFRcreat slope and the percentage change in total ketone bodies and 3OHBA in the luseogliflozin group. Since basic research has demonstrated that ketone bodies increased by SGLT2is have a renoprotective effect 32 , 33 , 34 , the increase in ketone bodies in this study might partially contribute to kidney function preservation.
Regarding safety, the addition of luseogliflozin did not increase the incidence of ESRD (dialysis incidence or progression to an eGFRcreat <10 mL/min/1.73 m2). The proportion of patients whose eGFRcreat decreased by ≥20–30% from baseline did not differ between the groups, except for the initial decline observed at week 4. These results demonstrate the safety of luseogliflozin even in patients with moderate‐to‐severe renal dysfunction.
This study had several potential limitations. First, this was an open‐label study that lacked blinding for patients and physicians, which may have introduced bias. However, we believe that the open‐label design did not significantly affect the results because the study employed objectively measurable endpoints, including eGFR. Second, this study was conducted exclusively in Japan, and all participants were Japanese, potentially limiting the generalizability of these findings to other countries or patients of different ethnicities. Third, the study did not achieve the target sample size of 200 patients, and only 152 patients were enrolled. One possible reason for the small sample size is the increased use of SGLT2is in Japan. Many physicians in the study reported difficulties in screening eligible candidates, as many had already been treated with SGLT2is. Additionally, our study was conducted during the COVID‐19 pandemic, which affected participant enrollment. The insufficient sample size may have affected the results of the study. Fourth, several baseline patients' characteristics, including SBP, hepatic disease comorbidities, and diabetic retinopathy, were not well‐balanced between the groups. Although this was a randomized‐controlled trial, because of the target number of cases, we set only three allocation factors (age, eGFRcreat, and UACR), and other factors could not be controlled. The possibility that the unbalance in the patients' background between the groups might affect the results in this study. We could not judge whether the reason for the lack of a significant between‐group difference in the primary endpoint was the insufficient power, the unbalance in the patients' background, or that luseogliflozin did not have renoprotective benefits in patients with type 2 diabetes mellitus and moderate‐to‐severe renal impairment. Further study with a larger, sufficient sample size, with well‐controlled patients' backgrounds may be required.
In conclusion, although the primary endpoint did not reach statistical significance, luseogliflozin may provide renoprotective benefits for patients with type 2 diabetes mellitus and moderate‐to‐severe renal impairment, potentially by slowing the rate of eGFR decline following the initial decline, without increasing further renal function decline to eGFRcreat <10 mL/min/1.73 m2 and dialysis incidence.
FUNDING
This work was supported by Taisho Pharmaceutical Co., Ltd. The funding sponsor had no role in the study design, collection, analysis, and interpretation of the data, writing of the report, or decision to submit the article for publication.
DISCLOSURE
Munehiro Kitada received personal fees outside of the work submitted by Taisho Pharmaceutical Co. Ltd. Masao Toyoda received grants outside the submitted work from LifeScan Japan K.K.; Mitsubishi Tanabe Pharma Corporation; Daiichi Sankyo Company, Limited; Novo Nordisk Pharma Ltd.; Sanofi K.K.; Takeda Pharmaceutical Company Limited; Eli Lilly Japan K.K.; MSD K.K.; Roche Diagnostics K.K.; and Dexcom, Inc. Hideki Kamiya received grants outside the submitted work from Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Company, Limited, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Mochida Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., and Takeda Pharmaceutical Company Limited, and personal fees outside the submitted work from Abbott Diagnostics Medical Co., Ltd., Astellas Pharma Inc., Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Eisai Co., Ltd., GlaxoSmithKline K.K., Kowa Company, Ltd., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Teijin Pharma Limited, Arkray Inc., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Company, Limited, Eli Lilly Japan K.K., Fukuda Denshi Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk Pharma Ltd., MSD K.K., Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Viatris Inc. Hideki Kamiya is also an editorial board member of the Journal of Diabetes Investigation, and due to decision‐making bias, they have not been included in the decision‐making process of the submission. Toshinari Takamura received grants outside the submitted work from Taisho Pharmaceutical Co., Ltd. and Kowa Company, Ltd. and personal fees outside the submitted work from Kowa Company, Ltd. Hiroshi Arima received grants outside the submitted work from Taisho Pharmaceutical Co., Ltd., and personal fees outside the submitted work from Taisho Pharmaceutical Co., Ltd. Daisuke Yabe received grants outside the submitted work from Novo Nordisk Pharma Ltd., Taisho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Arkray Inc., personal fees outside the submitted work from Kansaimedicalnet Co., Ltd./Kansai Electric Power Medical Research Institute, Taisho Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Sumitomo Pharma Co., Ltd., Sanofi K.K., Novo Nordisk Pharma Ltd., Kowa Company, Ltd., and Eli Lilly Japan K.K., and had a leadership or fiduciary role in Japan Diabetes Society, Japan Association for Diabetes Education and Care, Japan Endocrine Society, Asian Association for the Study of Diabetes, and International Diabetes Federation Western Pacific Region. Daisuke Yabe is also an editorial board member of the Journal of Diabetes Investigation, and due to decision‐making bias, they have not been included in the decision‐making process of the submission. Satoshi Miyamoto received grants outside the submitted work from Mitsubishi Tanabe Pharma Corporation and personal fees outside the submitted work from Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, and Bayer Yakuhin Ltd. Shinji Kume received grants outside the submitted work from Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Sumitomo Pharma Co., Ltd., and Mitsubishi Tanabe Pharma Corporation, personal fees outside the submitted work from Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., AstraZeneca K.K., Astellas Pharma Inc., Kowa Company, Ltd., Sumitomo Pharma Co., Ltd., and Taisho Pharmaceutical Co., Ltd., and had a leadership or fiduciary role in the Japanese Society of Nephrology, Japanese Society of Nephrology Guideline Committee, and Japan Diabetes Society Practical Guideline Committee. Atsushi Nakagawa received a grant for the submitted work from Taisho Pharmaceutical Co. Ltd. and grants outside the submitted work from Taisho Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co. Ltd., and Nippon Boehringer Ingelheim Co. Ltd. The authors declare no conflicts of interest.
Approval of the research protocol: The protocol of this study was approved (approval number: T013) by the Kanazawa Medical University Clinical Research Review Board.
Informed Consent: Written informed consent was obtained prior to intervention from all enrolled individuals who met the eligibility criteria.
Approval date of Registry and the Registration No. of the study/trial: August 24, 2020, jRCTs041200039.
Animal Studies: N/A.
Supporting information
Data S1. Supporting Information.
Figure S1. Changes in eGFRcreat using the PPS.
Figure S2. Changes in eGFRcys using the FAS.
Figure S3. Proportion of patients whose eGFRcreat decreased by ≥30%, ≥20%, became <10 mL/min/1.73 m2, and incidence of dialysis
Figure S4. Change in UACR.
Figure S5. Percentage change in ketone bodies.
Table S1. Participation in medical institutions.
Table S2. Eligibility criteria.
Table S3. Observational schedule and items.
Table S4. Study intervention provisions.
Table S5. Study outcomes.
Table S6. Correlation between the chronic eGFRcreat slope and percent change in ketone bodies.
Table S7. Adverse events.
ACKNOWLEDGMENTS
The authors express their sincere appreciation and condolences to Professor Daisuke Koya (Kanazawa Medical University and Omi Medical Center Hospital), who contributed to research planning and administration, but sadly passed away during this study. The authors would also like to thank Kenichi Shikata at Okayama University Hospital, Yumie Takeshita at Kanazawa University Hospital, Ken Takao and Makie Honda at Gifu University Graduate School of Medicine, Naoko Hanazumi at Kumanomae Nishimura Medical Clinic, Susumu Takagi at Kanazawa Medical University Himi Municipal Hospital, and all other clinical staff for their assistance in the execution of the study, and Soiken Inc. and EviPRO Co., Ltd. for their technical assistance in the launch and execution of the study. The authors would also like to thank Arata Yoneda from EviPRO Co., Ltd. for his support in the medical writing of this manuscript. The research fund provided by Taisho Pharmaceutical Co., Ltd. covered fees for technical assistance and medical writing. The manuscript was edited by a professional native English editor from Editage.
Clinical Trial Registry
Japan Registry of Clinical Trials (jRCT)
jRCTs041200039.
DATA AVAILABILITY STATEMENT
The datasets generated and/or analyzed during the current study are not publicly available because of the lack of a statement in the study protocol enabling data sharing with a third party after the end of the study, informed consent documents, and a lack of approval for data sharing by the ethics review board.
REFERENCES
- 1. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006; 116: 288–296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Gohda T, Murakoshi M, Koshida T, et al. Concept of diabetic kidney disease ‐paradigm shift from albuminuria‐based to GFR‐based kidney disease. Juntendo Med J 2019; 65: 510–516. [Google Scholar]
- 3. Kim MK, Kim DM. Current status of diabetic kidney disease and latest trends in management. J Diabetes Investig 2022; 13: 1961–1962. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol 2009; 20: 1813–1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. McGrath K, Edi R. Diabetic kidney disease: Diagnosis, treatment, and prevention. Am Fam Physician 2019; 99: 751–759. [PubMed] [Google Scholar]
- 6. Itano S, Kanda E, Nagasu H, et al. eGFR slope as a surrogate endpoint for clinical study in early stage of chronic kidney disease: From the Japan chronic kidney disease database. Clin Exp Nephrol 2023; 27: 847–856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Sartore G, Ragazzi E, Deppieri E, et al. Is eGFR slope a novel predictor of chronic complications of type 2 diabetes mellitus? A systematic review and meta‐analysis. J Diabetes Res 2024; 2024: 8859678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Coresh J, Turin TC, Matsushita K, et al. Decline in estimated glomerular filtration rate and subsequent risk of end‐stage renal disease and mortality. JAMA 2014; 311: 2518–2531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Guo Y, Cui L, Ye P, et al. Change of kidney function is associated with all‐cause mortality and cardiovascular diseases: Results from the Kailuan study. J Am Heart Assoc 2018; 7: e010596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295–2306. [DOI] [PubMed] [Google Scholar]
- 11. Heerspink HJL, Stefánsson BV, Correa‐Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383: 1436–1446. [DOI] [PubMed] [Google Scholar]
- 12. Wheeler DC, Toto RD, Stefánsson BV, et al. A pre‐specified analysis of the DAPA‐CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021; 100: 215–224. [DOI] [PubMed] [Google Scholar]
- 13. Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med 2023; 388: 117–127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Herrington WG, Staplin N, Agrawal N, et al. Long‐term effects of Empagliflozin in patients with chronic kidney disease. N Engl J Med 2024; 392: 777–787. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Nangaku M, Herrington WG, Goto S, et al. Effects of empagliflozin in patients with chronic kidney disease from Japan: Exploratory analyses from EMPA‐KIDNEY. Clin Exp Nephrol 2024; 28: 588–595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. EMPA‐KIDNEY Collaborative Group . Effects of empagliflozin on progression of chronic kidney disease: A prespecified secondary analysis from the EMPA‐KIDNEY trial. Lancet Diabetes Endocrinol 2024; 12: 39–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. American Diabetes Association Professional Practice Committee . 11. Chronic kidney disease and risk management: Standards of Care in Diabetes‐2025. Diabetes Care 2025; 48: S239–S251. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Samukawa Y, Haneda M, Seino Y, et al. Pharmacokinetics and pharmacodynamics of luseogliflozin, a selective SGLT2 inhibitor, in Japanese patients with type 2 diabetes with mild to severe renal impairment. Clin Pharmacol Drug Dev 2018; 7: 820–828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Miyamoto S, Heerspink HJL, de Zeeuw D, et al. A randomized, open‐label, clinical trial examined the effects of canagliflozin on albuminuria and eGFR decline using an individual pre‐intervention eGFR slope. Kidney Int 2024; 106: 972–984. [DOI] [PubMed] [Google Scholar]
- 20. Inaguma D, Imai E, Takeuchi A, et al. Risk factors for CKD progression in Japanese patients: Findings from the chronic kidney disease Japan cohort (CKD‐JAC) study. Clin Exp Nephrol 2017; 21: 446–456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Haneda M, Seino Y, Inagaki N, et al. Influence of renal function on the 52‐week efficacy and safety of the sodium glucose cotransporter 2 inhibitor luseogliflozin in Japanese patients with type 2 diabetes mellitus. Clin Ther 2016; 38: 66–88.e20. [DOI] [PubMed] [Google Scholar]
- 22. Kurose K, Inagaki N, Fukatsu A, et al. Evaluation of the safety and efficacy of SGLT2 inhibitor luseogliflozin in elderly patients with type 2 diabetes mellitus‐post‐marketing surveillance in elderly patients (final report). Jpn Pharmacol Ther 2017; 45: 559–569 (in Japanese). [Google Scholar]
- 23. Guppy M, Thomas ET, Glasziou P, et al. Rate of decline in kidney function with age: A systematic review. BMJ Open 2024; 14: e089783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Heerspink HJL, Jongs N, Chertow GM, et al. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: A prespecified analysis from the DAPA‐CKD trial. Lancet Diabetes Endocrinol 2021; 9: 743–754. [DOI] [PubMed] [Google Scholar]
- 25. Jardine MJ, Zhou Z, Mahaffey KW, et al. Renal, cardiovascular, and safety outcomes of Canagliflozin by baseline kidney function: A secondary analysis of the CREDENCE randomized trial. J Am Soc Nephrol 2020; 31: 1128–1139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988‐2014. JAMA 2016; 316: 602–610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Kume S, Araki SI, Ugi S, et al. Secular changes in clinical manifestations of kidney disease among Japanese adults with type 2 diabetes from 1996 to 2014. J Diabetes Investig 2019; 10: 1032–1040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Cheong AJY, Teo YN, Teo YH, et al. SGLT inhibitors on weight and body mass: A meta‐analysis of 116 randomized‐controlled trials. Obesity (Silver Spring) 2022; 30: 117–128. [DOI] [PubMed] [Google Scholar]
- 29. Mazidi M, Rezaie P, Gao HK, et al. Effect of sodium‐glucose cotransport‐2 inhibitors on blood pressure in people with type 2 diabetes mellitus: A systematic review and meta‐analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc 2017; 6: e004007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Zhang L, Zhang F, Bai Y, et al. Effects of sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors on serum uric acid levels in patients with chronic kidney disease: A systematic review and network meta‐analysis. BMJ Open Diabetes Res Care 2024; 12: e003836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Jang H, Kim Y, Lee DH, et al. Outcomes of various classes of Oral antidiabetic drugs on nonalcoholic fatty liver disease. JAMA Intern Med 2024; 184: 375–383. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Ekanayake P, Mudaliar S. A novel hypothesis linking low‐grade ketonaemia to cardio‐renal benefits with sodium‐glucose cotransporter‐2 inhibitors. Diabetes Obes Metab 2022; 24: 3–11. [DOI] [PubMed] [Google Scholar]
- 33. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium‐glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016; 65: 1190–1195. [DOI] [PubMed] [Google Scholar]
- 34. Tomita I, Kume S, Sugahara S, et al. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body‐induced mTORC1 inhibition. Cell Metab 2020; 32: 404–419.e6. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Information.
Figure S1. Changes in eGFRcreat using the PPS.
Figure S2. Changes in eGFRcys using the FAS.
Figure S3. Proportion of patients whose eGFRcreat decreased by ≥30%, ≥20%, became <10 mL/min/1.73 m2, and incidence of dialysis
Figure S4. Change in UACR.
Figure S5. Percentage change in ketone bodies.
Table S1. Participation in medical institutions.
Table S2. Eligibility criteria.
Table S3. Observational schedule and items.
Table S4. Study intervention provisions.
Table S5. Study outcomes.
Table S6. Correlation between the chronic eGFRcreat slope and percent change in ketone bodies.
Table S7. Adverse events.
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available because of the lack of a statement in the study protocol enabling data sharing with a third party after the end of the study, informed consent documents, and a lack of approval for data sharing by the ethics review board.