Long-term effects of esaxerenone in patients with type 2 diabetes, diabetic kidney disease, and hypertension (JDDM77)

Abstract

Objectives

This clinical study assessed the three-year, long-term effects of esaxerenone, a non-steroidal aldosterone receptor blocker, on Japanese patients with type 2 diabetes, diabetic kidney disease, and hypertension who were receiving renin-angiotensin system inhibitors.

Materials and methods

Data from a computerized diabetic care database were used to retrospectively compare esaxerenone users (Group A) with non-esaxerenone users (Group B). Propensity score weighting was applied to Group B. The study primarily focused on percent changes in the Urine Albumin-Creatinine Ratio (UACR) from baseline and also examined the estimated Glomerular Filtration Rate (eGFR), blood pressure, serum potassium levels, and HbA1c.

Results

There were 199 patients in Group A and 199 in Group B, matched 1:1 using propensity scores. UACR and blood pressure were significantly lower in Group A than in Group B. Geometric mean percent changes in UACR from baseline between the two groups were as follows: − 62.7% at 1 year (95% Confidence Interval (CI): − 91.0 to − 34.1%), − 48.9% at 2 years (95% CI: − 79.4 to − 19.3%), and − 63.8% at 3 years (95% CI: − 107.4 to − 20.2%). Additionally, the present study examined the impact of combining esaxerenone with SGLT2 inhibitors and GLP-1 receptor agonists and showed consistent effects on UACR irrespective of these medications. Esaxerenone slightly lowered eGFR with a low risk of hyperkalemia but did not adversely impact glucose metabolism.

Conclusions

Esaxerenone exerted antihypertensive and antialbuminuric effects in patients with type 2 diabetes, diabetic kidney disease, and hypertension.

Introduction

Chronic Kidney Disease (CKD), defined as a distinct disease concept by the Kidney Disease Outcome Quality Initiative in 2002, is a significant risk factor for requiring dialysis, kidney transplantation, and other forms of renal replacement therapy [1]. CKD is also associated with cardiovascular diseases and an increased mortality rate. When diabetes is one of the main causes of CKD, the condition is diagnosed as Diabetic Kidney Disease (DKD). DKD encompasses not only typical diabetic nephropathy but also atypical diabetes-related kidney diseases characterized by a decrease in the estimated Glomerular Filtration Rate (eGFR) without overt albuminuria [2]. In Japan, diabetic nephropathy has been the leading cause of initiating chronic dialysis therapy since 1989, accounting for 40.2% of cases in 2021 [3]. Therefore, preventing the progression of DKD is crucial for avoiding end-stage renal failure, cardiovascular diseases, and death and ensuring the quality of life of patients.

Hypertension is a frequent comorbidity in patients with type 2 diabetes [4] and is a well-known risk factor for cardiovascular diseases and microvascular complications [5–8]. Japanese guidelines for the management of hypertension (2019) recommend the strict control of blood pressure to < 130/80 mmHg in patients with diabetes and hypertension [9]. In cases of DKD with proteinuria, Renin-Angiotensin System (RAS) inhibitors are recommended as the first-line treatment due to their renal protective effects [9]. However, achieving optimal blood pressure control in patients with diabetes and hypertension may be challenging [10]. RAS inhibitors alone may not be sufficient for managing blood pressure and reducing proteinuria, underscoring the necessity for new treatment approaches.

Esaxerenone, a novel non-steroidal aldosterone receptor blocker, has shown promise in phase II and phase III clinical trials in Japan. When used in combination with RAS inhibitors, esaxerenone has been effective at further reducing blood pressure and albuminuria in hypertensive patients with type 2 diabetes and albuminuria [11, 12]. Additionally, the post-marketing EX-DKD trial highlighted its relative safety and efficacy for reducing blood pressure and albuminuria in patients with DKD and moderate renal impairment [13]. Nevertheless, the long-term clinical effects of esaxerenone on DKD remain unclear. Furthermore, limited information is currently available on whether esaxerenone offers additional antialbuminuric benefits when used in combination with medications such as Sodium Glucose Cotransporter 2 (SGLT2) inhibitors and Glucagon-Like Peptide-1 (GLP-1) receptor agonists. The FIDELIO-DKD trial on finerenone, another aldosterone receptor blocker, showed the significant suppression of renal composite endpoints over a median observation period of 2.6 years [14].

The present study investigated the albuminuria-attenuating effects of esaxerenone on DKD in real clinical settings over the course of three years. Changes in the Urine Albumin-Creatinine Ratio (UACR) and eGFR before and after the initiation of esaxerenone therapy were examined. Changes in blood pressure as an antihypertensive effect of esaxerenone, along with serum potassium (K) levels and HbA1c for safety evaluations, were also assessed.

Materials and methods

Participants and study procedures

The Japan Diabetes Clinical Data Management Study Group (JDDM), comprising Japanese diabetologists from specialized diabetes treatment facilities, established the Computerized Diabetic Care (CoDiC) database in 2001 [15]. Patient data are published on the JDDM website as basic research reports and are updated annually. Data from patients with type 2 diabetes mellitus who visited JDDM facilities between 2018 and 2023 were extracted from the CoDiC database for cross-sectional and retrospective analyses.

Patients in the esaxerenone administration group (Group A) had been continuously taking esaxerenone for more than 6 months. The non-esaxerenone group (Group B) consisted of patients who did not use esaxerenone during their medical visit in May 2020 (reference visit). Inclusion criteria were patients with DKD, defined as an average eGFR < 60 mL/min/1.73 m² measured within three months before the initiation of esaxerenone or before the reference visit or UACR > 30 mg/gCr measured within a year before the initiation of esaxerenone or before the reference visit. Exclusion criteria included patients with an average eGFR < 30 mL/min/1.73 m² measured within three months before the initiation of esaxerenone or before the reference visit, patients who started new RAS inhibitors, SGLT2 inhibitors, or GLP-1 receptor agonists within six months after the initiation of esaxerenone or after the reference visit, and patients prescribed mineralocorticoid receptor (MR) blockers other than esaxerenone.

Statistical analysis

Propensity-matched cohorts of Groups A and B were derived and compared using a 1:1 ratio with greedy matching on the propensity score, with a caliper of 0.2 standard deviations of the propensity score logit with no replacement [16]. Propensity scores were estimated using a logistic regression analysis, with the dependent variable being Group A/B and covariates including age, sex, weight, BMI, blood pressure, HbA1c, UACR, eGFR, and the use of RAS inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. We examined standardized differences and variance ratios to establish whether the matched cohort had balanced patient characteristics.

Changes from baseline to 3 years in the geometric mean of UACR were assessed at 1-year intervals, and the percent change in the geometric mean of UACR from baseline was estimated. Changes from baseline to 3 years in blood pressure, eGFR, serum K, and HbA1c were evaluated at 3-month intervals and the annual change in eGFR was estimated. A p-value < 0.05 was considered to be significant, and all statistical analyses were performed using SAS ver. 9.4 (SAS Institute, Inc., Cary, NC) and SPSS version 25. (IBM, Chicago, IL, USA).

Results

In the CoDiC database, there were 320 patients who met the inclusion criteria and were administered esaxerenone and 7,862 patients who did not receive esaxerenone. The present study involved 199 patients in Group A and 199 in Group B, matched 1:1 using propensity scores. Patient background factors in both groups are shown in Table 1.

Table 1.

Clinical characteristics of patients

	Group A (Esaxerenone)	Group B (non-Esaxerenone)	SMD
Number of cases	199	199
Age (Years)	67.24 ± 11.50	68.49 ± 11.34	-0.0032
Male:female	151:48	155:44	-0.0325
Duration of diabetes (years)	16.01 ± 9.29	16.91 ± 9.59	-0.0953
BMI (kg/m2)	26.43 ± 4.74	25.96 ± 4.19	-0.0083
HbA1c (%)	7.00 ± 0.72	6.96 ± 0.71	0.1051
eGFR (mL/min/1.73 m2)	66.21 ± 30.78	68.64 ± 41.10	-0.0669
Urinary albumin-creatinine ratio (mg/gCr)	364.98 ± 629.30	325.33 ± 610.53	0.064
UACR: < 30 mg/gCr	25 (12.6%)	39 (19.6%)	-0.2477
UACR: 30–299 mg/gCr	123 (61.8%)	111 (55.8%)	0.1113
UACR: ≥ 300 mg/gCr	51(25.6%)	49 (24.6%)	0.0283
Systolic blood pressure (mmHg)	137.04 ± 16.56	135.25 ± 15.70	0.1109
Diastolic blood pressure (mmHg)	75.06 ± 12.25	73.61 ± 11.14	0.1238
Systolic blood pressure ≥ 130 mmHg	137 (68.8%)	135 (67.8%)	0.1095
Number of antihypertensive drugs used in previous treatments	1.81 ± 0.86	1.90 ± 0.93	-0.1005
Cases of RAS inhibitor use	199 (100%)	199 (100%)	0
Cases of SGLT2 inhibitor use	149 (74.8%)	55 (27.6%)	0.9336
Cases of GLP-1 receptor agonist use	44 (22.1%)	19 (9.5%)	0.4458
Esaxerenone dosage	2.56 ± 1.30 mg (After 1 year) 2.88 ± 1.29 mg (After 2 years) 3.86 ± 1.40 mg (After 3 years)

Mean ± SD or proportion (%), BMI body mass index, eGFR estimated glomerular filtration rate, UACR Urinary Albumin-Creatinine Ratio, RAS renin-angiotensin system, SGLT2 sodium-glucose co-transporter-2, GLP-1 glucagon-like peptide-1, SMD standardized mean difference

Patient background characteristics after propensity score weighting between Groups A and B were well balanced. Average age was 67.2 years in Group A and 68.5 years in Group B. The duration of diabetes was 16.0 years in Group A and 16.9 years in Group B. Body mass index was 26.4 kg/m² in Group A and 26.0 kg/m² in Group B. Systolic blood pressure was 137.0 mmHg in Group A and 135.2 mmHg in Group B. eGFR was 66.2 mL/min/1.73 m² in Group A and 68.6 mL/min/1.73 m² in Group B. UACR was 365.0 mg/gCr in Group A and 325.3 mg/gCr in Group B. The usage rate of RAS inhibitors was 100% in both groups. However, there were some differences in concomitant drug use. The usage rate of SGLT2 inhibitors was 74.8% in Group A and 27.6% in Group B, while that of GLP-1 receptor antagonists was 22.1% in Group A and 9.5% in Group B.

Changes in blood pressure are shown in Fig. 1. In terms of blood pressure management, systolic blood pressure was significantly lower in Group A than in Group B from 6 months up to 36 months. The mean difference in systolic blood pressure between Groups A and B was − 4.95 mmHg at 12 months (95% Confidence Interval (CI): − 8.09 to − 1.80 mmHg), − 7.89 mmHg at 24 months (95% CI: − 11.81 to − 3.97 mmHg) and − 16.4 mmHg at 36 months (95% CI: − 23.22 to − 9.69 mmHg), as assessed by an independent t-test. The average difference in diastolic blood pressure between Groups A and B showed that Group A had significantly lower values at 5 observation points over the course of the study.

Fig. 1.

Changes in Blood Pressure. Changes in systolic blood pressure and diastolic blood pressure in continuous measures for 3 years. Data are shown as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 vs Group B (independent t-test)

Figure 2 shows percent changes in UACR from baseline. Percent changes in the geometric mean of UACR from baseline between the two groups were as follows: − 62.7% at 1st year (95% CI: − 91.0 to − 34.1%), − 48.9% at 2nd year (95% CI: − 79.4 to − 19.3%), and − 63.8% at 3rd year (95% CI: − 107.4 to − 20.2%).

Fig. 2.

Percent Change in the Geometric Mean of UACR from Baseline. Percent change in the geometric mean of UACR from baseline in continuous measures for 3 years. *Independent t-test

Table 2 shows the results obtained on the impact of combined SGLT2 inhibitors and GLP-1 receptor agonists on the percent change in UACR after the first year. The percent change in UACR after the first year showed no significant variations with or without the use of these combined medications in both groups, as assessed by an independent t-test.

Table 2.

Impact of combined SGLT2 inhibitors and GLP-1 receptor agonists on the 1-year percent change in the geometric mean of UACR in esaxerenone Group A and control Group B

	Presence or absence of concomitant medication	Cases	1-year percent change in the geometric mean of UACR (%)	Independent t-test
Group A	Total	184	− 19.3 ± 75.4
	SGLT2 inhibitor (−)	45	− 20.7 ± 52.1	P = 0.888
	SGLT2 inhibitor ( +)	139	− 18.8 ± 81.6
	GLP-1 receptor agonist (−)	145	− 20.0 ± 80.0	P = 0.810
	GLP-1 receptor agonist ( +)	39	− 16.7 ± 55.63
Group B	Total	145	43.3 ± 160.4
	SGLT2 inhibitor (−)	103	56.3 ± 183.3	P = 0.126
	SGLT2 inhibitor ( +)	42	13.3 ± 72.5
	GLP-1 receptor agonist (−)	132	46.2 ± 166.1	P = 0.485
	GLP-1 receptor agonist ( +)	13	13.5 ± 79.5

Mean ± SD, UACR urinary albumin-creatinine ratio, SGLT2 sodium-glucose co-transporter-2, GLP-1 glucagon-like peptide-1

Table 3 shows the results of the impact of baseline UACR on the percent change in UACR after the first year. Baseline UACR levels < 30 mg/gCr were classified as A1, between 30 and 299 mg/gCr as A2, and ≥ 300 mg/gCr as A3. No significant differences were observed between A1, A2, and A3 in both groups using a one-way ANOVA.

Table 3.

Impact of baseline UACR levels on the 1-year percent change in the geometric mean of UACR in esaxerenone group A and control group B

	Baseline UACR level	Cases	1-year percent change in the geometric mean of UACR (%)	One-way ANOVA
Group A	Total	184	− 19.3 ± 75.4
	A1: < 30 mg/gCre	20	− 19.8 ± 46.3	P = 0.742
	A2: between 30 and 299 mg/gCre	119	− 16.4 ± 85.5
	A3: ≥ 300 mg/gCre	45	− 26.6 ± 55.1
Group B	Total	145	43.3 ± 160.4
	A1: < 30 mg/gCre	31	94.5 ± 240.8	P = 0.066
	A2: between 30 and 299 mg/gCre	85	39.7 ± 143.5
	A3: ≥ 300 mg/gCre	29	− 1.1 ± 57.7

Mean ± SD, UACR urinary albumin-creatinine ratio

Figure 3 shows changes in eGFR over time in Groups A and B. Throughout the present study, eGFR decreased in both groups. Over the course of three years, eGFR was significantly lower in Group A than in Group B at two assessment points, as assessed by an independent t-test.

Fig. 3.

Changes in eGFR. Changes in eGFR in continuous measures for 3 years. Data are shown as the mean ± SD. *P < 0.05 vs Group B (independent t-test)

Figure 4 shows the annual rate of decline in eGFR during the present study. On average, a decline of − 3.70 mL/min/1.73 m²/year was observed in Group A and − 2.30 mL/min/1.73 m²/year in Group B. The mean difference between the groups was − 1.40 mL/min/year (95% CI: − 4.47 to 1.67 mL/min/year), showing no significant difference. Independent t-tests also indicated no significant differences in the annual eGFR decline between the groups after the 1st, 2nd, and 3rd years.

Fig. 4.

Annual Change in eGFR. The annual change in eGFR over the course of three years is shown for the overall period as well as individually for the first, second, and third years. *Independent t-test

Changes in serum K levels are shown in Fig. 5a. Serum K levels gradually increased in Group A but remained stable without significant fluctuations in Group B. At six points during the present study, serum K levels were significantly higher in Group A than in Group B. At 36 months, the average serum K level was 4.69 mEq/L in Group A and 4.35 mEq/L in Group B. The mean difference between the groups was 0.34 mEq/L (95% CI: 0.05 to 0.62 mEq/L), which was significant by an independent t-test.

Fig. 5.

Changes in Serum Potassium and HbA1c. Changes in (a) serum potassium and (b) HbA1c in continuous measures for 3 years. Data are shown as the mean ± SD. *P < 0.05, **P < 0.01 vs Group B (independent t-test)

Changes in HbA1c levels are shown in Fig. 5b. HbA1c levels did not show significant fluctuations in either group; there was only one point at 3 months where a significant difference was observed between the groups. However, at all other time points, no significant differences were noted between the two groups using an independent t-test.

Discussion

In the present study, we assessed the clinical effects of esaxerenone in Japanese patients with type 2 diabetes, DKD, and hypertension. Patients treated with esaxerenone (Group A) were retrospectively compared with those not treated with esaxerenone (Group B) using data from the CoDiC database. Propensity score matching was conducted to align the backgrounds of patients.

All patients were receiving RAS inhibitors, and the average number of antihypertensive drugs used was 1.8 to 1.9. Despite this, 68 to 69% of patients had inadequate blood pressure control (systolic blood pressure > 130 mmHg) and 80 to 87% had proteinuria (microalbuminuria). These results indicate a need for intensified treatment to manage blood pressure and proteinuria. We focused on evaluating esaxerenone in combination with RAS inhibitors as a potential option for treatment intensification.

In blood pressure management, systolic blood pressure after six months was significantly lower in Group A than in Group B. Furthermore, this antihypertensive effect continued to increase over the three-year period. A slight improvement was also observed in diastolic blood pressure. The package insert for esaxerenone states the following: “For diabetic patients with albuminuria or proteinuria, start with 1.25 mg once daily and, depending on the patient's condition such as serum K levels, increase to 2.5 mg once daily after four weeks from the start of the administration, and if the effect is insufficient, the dose can be increased up to 5 mg.” In the present study, the dosage of esaxerenone gradually increased over a period of three years. The average dose was 2.56 mg after the first year and slightly increased to 2.88 mg in the second year and 3.86 mg in the third year. The prescription continuation rate, defined as the proportion of days on esaxerenone during the observation period for all 199 patients, was 98.1%. These findings indicate a slow and steady escalation in the dosage of esaxerenone over the course of the present study, which appears to have contributed to the strengthening of the antihypertensive effect over time.

The percent change in the geometric mean of UACR from baseline decreased in Group A but increased in Group B. This significant reduction in Group A was observed at all time points, namely, after the 1st, 2nd, and 3rd years.

In Group A, no significant difference was noted in the percent change in the geometric mean of UACR from baseline after the first year regardless of whether esaxerenone was administered in combination with SGLT2 inhibitors and GLP-1 receptor agonists. This result suggests that the UACR-lowering effects of esaxerenone may be expected not only when used alone, but also in combination with these medications. Additionally, regardless of whether baseline UACR was within the normal range or showed microalbuminuria or overt albuminuria, there was no significant difference in the percent decrease in UACR in the first year. Therefore, the ability of esaxerenone to reduce UACR may be expected across all stages of albuminuria.

In patients with CKD, albuminuria has been identified as a strong prognostic factor for the progression of kidney disease [17, 18]. In patients with DKD, the suppression of UACR is associated with a reduction in the occurrence of end-stage renal disease [19–21]. Therefore, regular measurements of urinary albumin in patients with DKD are useful for prognostication. Previous studies demonstrated that esaxerenone, when administered in combination with RAS inhibitors, reduced UACR over 12 weeks [11–13]. The present study showed that this effect on UACR was sustained over a three-year period. In consideration of UACR as a surrogate marker for the risk of end-stage renal disease and dialysis, esaxerenone may reduce these future risks.

In patients with diabetes, CKD, and obesity, even if blood aldosterone levels are within the normal range, these patients may have MR-associated hypertension due to activated MR [22]. The sustained activation of renal MR has been implicated in diabetes via RAS-dependent and independent mechanisms and may ultimately cause kidney damage independent of blood pressure. In recent years, non-steroidal MR blockers have attracted increasing interest due to their better pharmacological profiles. Finerenone, the first compound of this class, effectively reduced the progression of kidney disease and improved cardiovascular outcomes in participants with type 2 diabetes in phase 3 trials [14, 23]. The difference between finerenone and esaxerenone lies in their blood pressure-lowering effects, with finerenone being less potent than esaxerenone. In the FIDELIO-DKD trial, changes in mean systolic blood pressure from baseline to month 1 and to month 12 were only − 3.0 and − 2.1 mmHg, respectively, with finerenone [14]. Therefore, in cases of DKD being treated with RAS inhibitors, where the suppression of albuminuria is insufficient, it is advisable to select finerenone when further reductions in blood pressure are not necessary and esaxerenone when additional blood pressure reductions are needed to achieve the target blood pressure.

In this trial, the annual change in eGFR showed no significant differences between Groups A and B in the 1st, 2nd, or 3rd year. However, eGFR measured quarterly was significantly lower at two points in Group A than in Group B. This is considered to reflect the “initial drop” phenomenon, which has also been reported for RAS inhibitors and SGLT2 inhibitors [24], with eGFR temporarily decreasing after the initiation of esaxerenone. This decrease is not a true decline in renal function and is transient. In phase II and phase III trials in Japan, eGFR returned to baseline after the discontinuation of esaxerenone at 12 weeks [11, 12]. In this trial, the decrease in eGFR was the most significant in the 1st year in Group A, and gradually became smaller in the 2nd and 3rd years, which may be due to the “initial drop” effect.

Serum K levels in Group A showed a gradual increase over three years and were significantly higher by 0.34 mEq/L than those in Group B after 36 months. Hyperkalemia is a dose-dependent side effect of MR blockers [25]. When MR blockers are used in combination with RAS inhibitors, the risk of developing hyperkalemia needs to be considered.

Regarding the progression of HbA1c, neither group showed significant fluctuations, suggesting the safety of esaxerenone in terms of glucose metabolism.

There are several limitations that need to be addressed. The observation period was shorter for Group A than for Group B. In Group B, the percentage of patients with UACR data was 73% in 1st year, 65% in 2nd year, and 56% in 3rd year, whereas in Group A, it decreased over time from 92% in 1st year to 62% in 2nd year and 35% in 3rd year. Esaxerenone is a relatively new antihypertensive drug that was launched in May 2019. Therefore, in the present study, which used a database up to 2023, only 76 cases had at least one visit in the 3rd year, and only 24 cases had a visit at 36 months. Therefore, the variability of results increased as the number of cases decreased. Furthermore, although we performed propensity score weighting in the present study, it was difficult to achieve a perfect match and standardized mean differences in some items exceeded 0.1. A difference in the frequency of use of SGLT2 inhibitors and GLP-1 receptor agonists was observed between the groups. We cannot rule out the possibility that this bias may have influenced the evaluation of the renoprotective effects of esaxerenone in Group A. In our study, no significant difference was observed in the change in UACR, the primary endpoint, regardless of the use of these drugs in either group. Previous studies have reported that the UACR-lowering effects of MR blockers and SGLT2 inhibitors are additive [26]. However, our findings showed no significant difference in the UACR-lowering effects of esaxerenone with or without concurrent SGLT2 inhibitors, indicating no observable additive effect in this cohort. This discrepancy is likely attributable to differences in the timing of drug administration; previous studies showing additive effects involved the simultaneous administration of both MR blockers and SGLT2 inhibitors. In contrast, in our study, SGLT2 inhibitors were administered as pre-existing therapy prior to introducing esaxerenone. Consequently, when esaxerenone is administered after the UACR-lowering effects of the SGLT2 inhibitor have stabilized, an additive UACR-lowering effect may still be anticipated with the addition of esaxerenone. Another limitation is that this was not a prospective randomized control trial; therefore, there may have been a patient selection bias by physicians. Moreover, there was a significant difference in blood pressure management between the groups; therefore, we cannot deny the possibility that the effects of reducing albuminuria were simply due to this difference.

In conclusion, esaxerenone exerted inhibitory effects on urine albumin and reduced blood pressure over three years in patients with type 2 diabetes, DKD, and hypertension. These inhibitory effects were observed regardless of the use of SGLT2 inhibitors and GLP-1 receptor agonists or the amount of urine albumin prior to treatment initiation.

Data availability

All data supporting the results of this study are available within the paper.

Declarations

Conflict of interest

Author DU has received lecture fees from Novo Nordisk Pharma Ltd., Novartis Pharma KK, Eli Lilly Japan KK., Daiichi Sankyo Co., Ltd., Tanabe Mitsubishi Pharma Co., Ltd., Otsuka Pharma Co., Ltd., Kowa Co., Ltd., Sanofi KK., Sumitomo Pharma Co., Ltd., Kissei Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Author YS has received lecture fees from Mochida Pharma Co., Ltd. and clinical research expenses from Eli Lilly Japan KK. Author NK has received lecture fees from Novo Nordisk Pharma Ltd. Author HM has received lecture fees from Sanofi, Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma LTD., Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc, Eli Lilly Japan K.K. MSD, and total amount of scholarships (incentives) from Takeda Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Kowa Company, Ltd., Nipro Corporation, and Teijin Pharma Co., Ltd. Author AK, Author SN, and Author SK declare that they have no conflicts of interest.

Ethical Standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Written informed consent was not required from patients because of the retrospective nature of this study. The option to ‘opt out’ and the procedures for doing so were made clear through a poster describing the study in each clinic. The protocol for this research project was approved by a suitably constituted Ethics Committee of the institution, the JDDM Ethics Committee (approval No. JDDM2023-2, 4 June 2023).