Visual Abstract
Keywords: esaxerenone, diabetes mellitus, microalbuminuria
Abstract
Background and objectives
Diabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently reduced the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and microalbuminuria. This 52-week phase 3 study further investigated the effects of esaxerenone on the urinary albumin-to-creatinine ratio in this patient group.
Design, setting, participants, & measurements
In this multicenter, randomized, double-blind study, patients with type 2 diabetes and a urinary albumin-to-creatinine ratio of 45 to <300 mg/g creatinine treated with renin-angiotensin system inhibitors were randomized to esaxerenone or placebo for 52 weeks (n=455). Esaxerenone was initiated at 1.25 mg/d and titrated to 2.5 mg/d on the basis of serum potassium monitoring. The primary endpoint was the proportion of patients achieving urinary albumin-to-creatinine ratio remission (<30 mg/g creatinine and ≥30% reduction from baseline on two consecutive occasions).
Results
Overall, 49 (22%) and nine (4%) patients in the esaxerenone and placebo groups, respectively, achieved urinary albumin-to-creatinine ratio remission (absolute difference 18%; 95% confidence interval, 12% to 25%; P<0.001). The percent change in urinary albumin-to-creatinine ratio from baseline to end of treatment was significantly higher with esaxerenone versus placebo (−58% versus 8%; geometric least-squares mean ratio to placebo 0.38, 95% confidence interval, 0.33 to 0.44). There was a significant improvement with esaxerenone versus placebo in time to first remission (hazard ratio, 5.13; 95% confidence interval, 3.27 to 8.04) and time to first transition to urinary albumin-to-creatinine ratio ≥300 mg/g creatinine (hazard ratio, 0.23; 95% confidence interval, 0.11 to 0.48). More patients had a serum potassium level ≥6.0 or ≥5.5 mEq/L on two consecutive measurements in the esaxerenone group (20 [9%]) versus placebo (5 [2%]); these events were asymptomatic and resolved after dosage reduction or treatment discontinuation.
Conclusions
Adding esaxerenone to existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria increased the likelihood of albuminuria returning to normal levels, and reduced progression of albuminuria to higher levels.
Introduction
Diabetic kidney disease (DKD) occurs in about 40% of patients with type 2 diabetes as their condition progresses (1). DKD is characterized by persistent albuminuria, increasing serum creatinine, and gradually decreasing eGFR (2,3); the result is kidney failure. The high worldwide prevalence of type 2 diabetes and the large number of patients progressing to DKD is associated with a high economic burden (4); thus, slowing disease progression with appropriate medical intervention is critical, from both a health care system and societal perspective.
In addition to being the leading cause of ESKD, DKD is an important risk factor for cardiovascular events and related mortality (1). One of the typical signs of DKD is albuminuria, and the presence of albuminuria has been shown to be associated with higher cardiovascular risk (5). Regression or remission of albuminuria in early DKD has the potential to reduce rates of both cardiovascular and kidney-related events (6–10). Although controversy persists over whether therapies to decrease albuminuria can ultimately reduce rates of kidney failure in the clinical environment (11,12), data from a recent meta-analysis, using change in albuminuria as a surrogate endpoint over a median follow-up period of 3.4 years, indicated that a 30% reduction in the geometric mean albuminuria (for interventional treatment versus control) was associated with a 27% reduction in the risk of developing ESKD in patients with diabetes (13).
The current approach to managing DKD includes lifestyle modifications, plus tight control of blood glucose levels, BP, and serum lipid levels (2,14–18). Inhibitors of the renin-angiotensin system (RAS) are commonly used in patients with DKD and are associated with reductions in BP, regression of albuminuria, and reductions in rates of ESKD and cardiovascular events (19–24). The nonselective, steroidal mineralocorticoid receptor blockers, spironolactone and eplerenone, when administered either individually or in conjunction with one or more RAS inhibitors, have also been shown to be effective in reducing urinary protein/albumin excretion and BP in patients with DKD; however, an increased risk of hyperkalemia has limited their use in this patient group (25–27). Thus, effectively preventing progression of kidney disease in patients with DKD remains an important clinical challenge, and there is a need for additional effective treatment options (14).
A phase 2b study in Japanese patients with type 2 diabetes showed the new nonsteroidal mineralocorticoid receptor blocker esaxerenone, as an add-on therapy to RAS inhibitors for 12 weeks, dose dependently reduced the urinary albumin-to-creatinine ratio (UACR) by 38%–56% versus RAS inhibitors alone (28). Therefore, esaxerenone is a potential new therapy for patients with DKD. This Double-Blind, Randomized Phase 3 Study Comparing Esaxerenone with Placebo in Japanese Type 2 Diabetic Patients with Microalbuminuria (ESAX-DN) was conducted to confirm the efficacy and safety of adding esaxerenone to RAS inhibitor therapy, compared with ongoing RAS inhibitor therapy alone, on the UACR in a large group of Japanese patients with type 2 diabetes and a UACR of 45 to <300 mg/g creatinine, for 52 weeks of treatment.
Materials and Methods
Study Design
The ESAX-DN study was a multicenter (135 sites), randomized, double-blind, placebo-controlled study (JapicCTI-173695) conducted in Japan from September 2017 to April 2019 (Supplemental Figure 1). The study protocol was approved by the local institutional review board at each participating site. The study was conducted in accordance with the principles of the Declaration of Helsinki and ICH-E6-guideline for Good Clinical Practice (CPMP/ICH/135/95). All patients provided written informed consent before enrollment.
Patients
Eligible patients were aged ≥20 years and had both hypertension and type 2 diabetes. All had received prior RAS inhibitor treatment for ≥12 weeks, had shown a UACR of 45 to <300 mg/g creatinine in the first morning urine sample on at least two occasions during the prestudy observational run-in period, and had an eGFR ≥30 ml/min per 1.73 m2 (eGFR was calculated as follows: 194× serum creatinine−1.094 × age−0.287, multiplied by 0.739 for female patients) (29). Exclusion criteria were as follows: presence of type 1 diabetes, glycated hemoglobin (National Glycohemoglobin Standardization Program criteria) ≥8%, secondary glucose intolerance (exocrine pancreatic disease, endocrine disease, severe infection, etc.), GN, lupus nephritis, nephrotic syndrome, active nephritis, non-DKD, secondary or malignant hypertension, sitting systolic BP ≥160 or <120 mm Hg and sitting diastolic BP ≥100 or <60 mm Hg, serum potassium <3.5 or ≥5.1 mEq/L in patients with eGFR ≥45 ml/min per 1.73 m2, and serum potassium <3.5 or ≥4.8 mEq/L in patients with eGFR ≥30 and <45 ml/min per 1.73 m2.
Treatment
After a 4-week run-in period, patients were randomized (1:1) to treatment with esaxerenone or placebo for 52 weeks. Randomization was performed by an independent statistician using internet-based interactive response technology, and patients were stratified by eGFR and UACR during the run-in period (UACR ≥100 or <100 mg/g creatinine, and an eGFR of 30 to <45, 45 to <60, or ≥60 ml/min per 1.73 m2). This was a double-blind study with patients, investigators, and sponsors blinded to treatment. Existing treatment with RAS inhibitors was continued at a constant dosage throughout the study.
Esaxerenone was initiated at a dosage of 1.25 mg/d to minimize the risk of increasing serum potassium levels, and then gradually increased to 2.5 mg/d on the basis of serum potassium level monitoring (see Supplemental Methods for full details). The 2.5 mg/d dosage was considered appropriate on the basis of the findings of an earlier study (23).
Data Collection
Details of the study visits are shown in Supplemental Table 1. Determination of UACR was made from first morning urine samples. Venous blood samples were collected, processed for serum isolation, and stored at −20°C or below before being transferred to a central laboratory for analysis. Vital signs were monitored at each study visit, and all adverse events were recorded. Potential causal relationships between adverse events and study drug were determined by the principal investigator or sub-investigator.
Efficacy
The primary endpoint was the proportion of patients with UACR remission at the end of treatment. For patients who discontinued treatment before 52 weeks, the evaluation was conducted using the two consecutive time points immediately before and at the end, or at discontinuation, of treatment. Remission was defined as UACR <30 mg/g creatinine and a ≥30% reduction in UACR from baseline at two consecutive time points. The key secondary endpoint was the percent change in UACR from baseline to the end of treatment (mean value of two consecutive time points measured immediately at the end of treatment). Additional endpoints were changes in BP and creatinine levels, and the rate of transition to UACR ≥300 mg/g creatinine at two consecutive time points after treatment. Post hoc analyses included the correlations between the change in UACR and changes in BP and between change in UACR and change in eGFR. In addition, to exclude the possible influences of seasonal fluctuations, a difference in UACR reduction between groups over time was included as a post hoc analysis.
Safety
Safety endpoints included adverse events, serum potassium, and percent change in eGFR from baseline to the end of treatment and time-course change in eGFR. Post hoc analysis determined the proportion of patients with a ≥30% reduction in eGFR from baseline for two consecutive measurements.
Statistical Analyses
Target sample size was on the basis of the number of patients required to ensure adequate power to demonstrate the superiority of esaxerenone over placebo for UACR response (primary endpoint). The proportion of patients with UACR remission was estimated to be 15% in the placebo group and 30% in the esaxerenone group on the basis of existing data (23,30,31). To achieve a power of 90% with a two-sided significance level of 5%, the estimated sample size was 161 patients per group. The target was 200 patients per group, allowing for 20% dropout.
The full analysis set was the primary analysis set for all efficacy analyses, and included all randomized patients who received ≥1 dose of study medication and who had ≥1 on-treatment UACR measurement available. The safety set included all patients who received ≥1 dose of study medication.
For the primary endpoint, the null hypothesis that there was no difference in the proportion of patients achieving UACR remission at the end of treatment between the two treatment groups was tested using a chi-squared test. Patients without two consecutive measurements during treatment were considered not to have achieved remission. Between-group differences for the key secondary endpoint were assessed using an analysis of covariance model, which included change in log-transformed UACR as a response variable, treatment group as a factor, and baseline log-transformed UACR as a covariate; patients without two consecutive on-treatment measurements were excluded. To adjust for a multiplicity of statistical tests, treatment comparison for the key secondary endpoint was performed only after a statistically significant difference was confirmed for the primary endpoint. Time to and duration of the first remission of a UACR of 45 to <300 mg/g creatinine was analyzed using the Kaplan–Meier method, and a hazard ratio (HR) was estimated by Cox proportional hazards model. As a post hoc analysis, time to transition to UACR ≥300 mg/g creatinine was analyzed in the same manner. Safety data were summarized using descriptive statistics. For comparison between groups, a chi-squared test was conducted for categoric variables as a pos hoc analysis.
All statistical analyses were performed using SAS (version 9.4, SAS Institute, Cary, NC).
Results
Patient Characteristics
A total of 455 patients were randomized to treatment and comprised the safety analysis set. Six patients were excluded from the full analysis set (n=449) due to a lack of primary endpoint data for all time points (Supplemental Figure 2). A total of 19 patients in the placebo group (8%) and 43 in the esaxerenone group (19%) discontinued treatment during the study (P=0.001), most commonly due to the occurrence of an adverse event (eight and 21 patients, respectively) (Supplemental Table 2). Baseline characteristics were similar between the esaxerenone and placebo groups (Table 1). The final dose of esaxerenone was 2.5 mg/d in about 90% of cases.
Table 1.
Baseline characteristics of patients with type 2 diabetes and microalbuminuria who participated in the Double-Blind, Randomized Phase 3 Study Comparing Esaxerenone with Placebo in Japanese Type 2 Diabetic Patients with Microalbuminuria
| Characteristics | Placebo, n=227 | Esaxerenone 1.25–2.5 mg/d, n=222 | All, n=449 |
|---|---|---|---|
| Sex, male | 180 (79) | 165 (74) | 345 (77) |
| Age, yr | 66±9 | 66±10 | 66±9 |
| Weight, kg | 70±14 | 70±13 | 70±13 |
| Body mass index, kg/m2 | 25.9±4.0 | 26.2±4.1 | 26.1±4.0 |
| Sitting systolic BP, mm Hg | 140±10 | 140±10 | 140±10 |
| Sitting diastolic BP, mm Hg | 84±8 | 83±8 | 84±8 |
| UACR, mg/g creatinine | 110 (47, 278) | 113 (46, 286) | 111 (46, 286) |
| eGFR, ml/min per 1.73 m2 | 69±18 | 69±18 | 69±18 |
| Serum potassium, mEq/L | 4.3±0.3 | 4.4±0.3 | 4.4±0.3 |
| HbA1c, % | 7.0±0.6 | 7.0±0.6 | 7.0±0.6 |
| LDL cholesterol, mg/dl | 103±28 | 109±26 | 106±27 |
| Duration of hypertension, yr | 11±8 | 11±8 | 11±8 |
| Duration of diabetes, yr | 14±9 | 14±8 | 14±9 |
| Other complications | |||
| Diabetic retinopathya | 107 (47) | 102 (46) | 209 (47) |
| Diabetic neuropathy | 65 (29) | 58 (26) | 123 (27) |
| Hyperlipidemia | 175 (77) | 170 (77) | 345 (77) |
| Hyperuricemia | 68 (30) | 78 (35) | 146 (33) |
| Coronary artery disease | 17 (8) | 19 (9) | 36 (8) |
| Heart failure (≤ NYHA class II) | 1 (0.4) | 2 (0.9) | 3 (0.7) |
| Atrial fibrillation | 6 (3) | 6 (3) | 12 (3) |
| Antihypertensive agents | |||
| ARB | 214 (94) | 209 (94) | 423 (94) |
| ACE inhibitor | 13 (6) | 13 (6) | 26 (6) |
| Other antihypertensive agents | |||
| Calcium channel blocker | 155 (68) | 148 (67) | 303 (67) |
| Diuretics | 26 (11) | 16 (7) | 42 (9) |
| Alpha blocker | 15 (7) | 16 (7) | 31 (7) |
| Beta blockers | 25 (11) | 24 (11) | 49 (11) |
| Number of antihypertensive agents | |||
| Monotherapy | 61 (27) | 64 (29) | 125 (28) |
| Double therapy | 113 (50) | 113 (51) | 226 (50) |
| Triple therapy or more | 53 (23) | 45 (20) | 98 (22) |
| Hypoglycemic agent | 218 (96) | 213 (96) | 431 (96) |
| DPP-4 inhibitor | 152 (67) | 144 (65) | 296 (66) |
| SGLT2 inhibitor | 56 (25) | 50 (23) | 106 (24) |
| GLP-1 receptor agonist | 18 (8) | 14 (6) | 32 (7) |
Data are n (%), mean±SD or median (min, max). UACR, urinary albumin-to-creatinine ratio; HbA1c, hemoglobin A1c; NYHA, New York Heart Association; ARB, angiotensin receptor blocker; ACE, angiotensin-converting enzyme; DPP-4, dipeptidyl peptidase 4; SGLT2, sodium-glucose cotransporter 2; GLP-1, glucagon-like peptide-1.
On the basis of the Davis classification; included patients diagnosed with simple retinopathy, preproliferative retinopathy, or proliferative retinopathy.
Efficacy
The proportion of patients with remission at the end of treatment was significantly higher in the esaxerenone versus placebo group (22% versus 4%; difference 18%; 95% confidence interval [95% CI], 12% to 25%; P<0.001) (Table 2). Cumulative remission rates at 52 weeks were higher in the esaxerenone group (44%; 95% CI, 38% to 52%) than in the placebo group (11%; 95% CI, 7% to 16%), and there was a significant improvement in the time to first remission with esaxerenone versus placebo (HR, 5.13; 95% CI, 3.27 to 8.04; Figure 1A). The median duration of the first remission by Kaplan–Meier method was 15.1 weeks (95% CI, 4.1 to 36.1) in the placebo group, and the median was not reached in the esaxerenone group (Figure 1B). The proportion of patients with a ≥30% reduction in UACR was also higher in the esaxerenone (69%; 95% CI, 63% to 75%) versus placebo group (20%; 95% CI, 15% to 26%), as was the proportion with UACR <30 mg/g creatinine (22%; 95% CI, 17% to 28% versus 4%; 95% CI, 2% to 7%) (Table 2). The percent change in UACR from baseline to the end of treatment in the esaxerenone group was significantly higher than that in the placebo group (−58% versus 8%; relative reduction compared with placebo; geometric least-squares mean ratio to placebo 0.38; 95% CI, 0.33 to 0.44; P<0.001) (Table 2). In the esaxerenone group, UACR decreased slowly until week 24, remained stable until the end of treatment, and was still significantly reduced versus baseline at the 4-week post-treatment follow-up (Figure 2); the difference in UACR reduction between the esaxerenone and placebo groups increased gradually over time (Supplemental Figure 3). The proportion of patients who transitioned to UACR ≥300 mg/g creatinine at the end of treatment was significantly lower with esaxerenone versus placebo (3 [1%] versus 17 [7%]; difference −6% [−11% to −2%]). Post hoc analysis showed a 76% reduction in the hazard of transition to UACR ≥300 mg/g creatinine and a significant improvement in the time to first transition to UACR ≥300 mg/g creatinine with esaxerenone versus placebo (HR, 0.23; 95% CI, 0.11 to 0.48) (Supplemental Figure 4).
Table 2.
Summary of primary and secondary efficacy endpoints (full analysis set)
| Endpoints | Placebo, n=227 | Esaxerenone 1.25–2.5 mg/d, n=222 | Treatment difference (95% CI) | P value | |
|---|---|---|---|---|---|
| Patients with remission at the end of treatment, n (%)a | 9 (4) | 49 (22) | 18 (12 to 25) | <0.001 | |
| Patients with UACR <30 mg/g creatinine, n (%) | 9 (4) | 49 (22) | 18 (12 to 25) | <0.001 | |
| Patients with ≥30% reduction in UACR, n (%) | 45 (20) | 154 (69) | 50 (41 to 57) | <0.001 | |
| Geometric mean of UACR at baseline, mg/g creatinine | 110 (103 to 117) | 117 (109 to 124) | — | — | |
| Geometric mean of UACR at end of treatment, mg/g creatinine | 120 (107 to 134) | 48 (43 to 55) | — | — | |
| Geometric least-square mean ratio from baseline to end of treatment in UACRb | 1.08 (0.98, 1.20) | 0.42 (0.38, 0.46) | 0.38c (0.33 to 0.44) | <0.001 | |
Data are shown as n (%) or as geometric means, geometric and least-square mean changes, or treatment differences (all shown with 95% confidence intervals in parentheses); P values are also indicated. UACR, urinary albumin-to-creatinine ratio.
Remission was defined as two consecutive UACR <30 mg/g creatinine values and ≥30% reduction in UACR from baseline.
Least-squares means of the change from baseline log-transformed values at the end of treatment, on the basis of the analysis of covariance (ANCOVA) model with treatment group as a factor and log-transformed baseline values as covariates. The estimates are back transformed, and expressed as the ratio in the original scale.
Least-squares means of the between-treatment difference of the change log-transformed values (esaxerenone–placebo), on the basis of the same ANCOVA model. The estimates are back transformed, and expressed as the ratio in the original scale.
Figure 1.
Esaxerenone improved the time to and duration of the first remission. Kaplan–Meier analyses of the (A) time to first remission and (B) duration of remission. HR, hazard ratio; 95% CI, 95% confidence interval.
Figure 2.
Esaxerenone decreased urinary albumin-to-creatinine ratio (UACR) slowly until week 24. The UACR remained stable until the end of treatment and was still significantly reduced versus baseline at 4 weeks post-treatment. Time course of UACR values (A) and geometric mean percent change from baseline in UACR (B). End-of-treatment (EOT) values were calculated by taking the average of measurements at the last two visits in the treatment period. Data are shown as geometric mean±95% confidence intervals.
The proportion of patients with UACR remission did not differ markedly between different patient subgroups on the basis of baseline UACR, eGFR, BP, or dipeptidyl peptidase 4 (DPP-4) or sodium-glucose transport protein 2 (SGLT2) inhibitor coadministration (Supplemental Table 3), and coadministration of DPP-4 or SGLT2 inhibitors did not appear to influence the extent of change from baseline of UACR in the esaxerenone group, with similar geometric least-square mean ratios to baseline observed between subgroups (Supplemental Table 4).
At the end of treatment, there were significant reductions from baseline in sitting systolic and diastolic BP (−10 [−12 to −9] and −5 [−6 to −4] mm Hg, respectively) in the esaxerenone group. During treatment with a constant dosage of RAS inhibitors, incremental reductions in sitting systolic BP and diastolic BP were observed up to week 32 of esaxerenone therapy; BP then remained stable until the end of treatment but increased after treatment withdrawal (Supplemental Figure 5). In a post hoc analysis, coadministration of DPP-4 or SGLT2 inhibitors did not appear to influence the extent of change from baseline in sitting systolic and diastolic BP in the esaxerenone group (Supplemental Table 4). In addition, no strong correlation was observed between the change in UACR and change in BP at the end of treatment, and this trend was the same at all time points during the treatment period (Supplemental Figure 6). However, there were weak correlations between the rate of change in UACR and changes in eGFR (Supplemental Figure 7).
Safety
The proportion of patients with at least one treatment-emergent adverse event was similar in the esaxerenone and placebo groups (78% and 77%, respectively) (Table 3). The most frequent adverse events were upper respiratory tract infection, increased serum potassium, influenza, and back pain. No cardiovascular-related adverse events were recorded during treatment in either arm.
Table 3.
Summary of treatment-emergent adverse events, adverse events with a frequency of ≥3%, and occurrences of increased serum potassium
| Category of Adverse Events | Placebo, n=229a | Esaxerenone 1.25–2.5 mg/d, n=226a |
|---|---|---|
| Total number of treatment-emergent adverse events | 528 | 530 |
| Patients with at least one treatment-emergent adverse event | 177 (77) | 177 (78) |
| Patients with at least one drug-related treatment-emergent adverse event | 16 (7) | 44 (19) |
| Patients with at least one serious treatment-emergent adverse event | 24 (10) | 18 (8) |
| Patients with at least one drug-related serious treatment-emergent adverse event | 0 (0) | 0 (0) |
| Patients with at least one severe treatment-emergent adverse event | 6 (3) | 8 (4) |
| Patients with at least one drug-related severe treatment-emergent adverse event | 0 (0) | 0 (0) |
| Patients who discontinued from study treatment due to a treatment-emergent adverse event | 8 (3) | 21 (9) |
| Patients who discontinued study treatment due to a drug-related treatment-emergent adverse event | 2 (1) | 13 (6) |
| Patients who died | 0 (0) | 1 (0.4) |
| Patients who died due to a drug-related treatment-emergent adverse event | 0 (0) | 0 (0) |
| Frequent adverse events (>3%) | ||
| Influenza | 10 (4) | 15 (7) |
| Viral upper respiratory tract infection | 61 (27) | 66 (29) |
| Hyperuricemia | 6 (3) | 7 (3) |
| Cataract | 11 (5) | 3 (1) |
| Upper respiratory tract inflammation | 9 (4) | 14 (6) |
| Abdominal discomfort | 9 (4) | 6 (3) |
| Constipation | 7 (3) | 6 (3) |
| Back pain | 13 (6) | 12 (5) |
| Blood creatinine increased | 3 (1) | 7 (3) |
| Blood potassium increased | 5 (2) | 27 (12) |
| Contusion | 8 (3) | 7 (3) |
| Increased serum potassium | ||
| Serum potassium ≥6.0 or ≥5.5 mEq/L on two consecutive measurements | 5 (2) | 20 (9) |
| Population with serum potassium ≥4.5 mEq/L at baseline | 4/87 (5) | 13/94 (14) |
| Population with serum potassium <4.5 mEq/L at baseline | 1/142 (1) | 7/132 (5) |
| Population with eGFR <60 ml/min per 1.73 m2 at baseline | 5/75 (7) | 14/73 (19) |
| Population with eGFR ≥60 ml/min per 1.73 m2 at baseline | 0/154 (0) | 6/153 (4) |
| Discontinuation due to increased serum potassium | 1 (0.4) | 10 (4) |
Data are n (%).
These values are the denominator for percentage calculations unless stated otherwise.
Serum potassium levels increased over the first 2 weeks after esaxerenone initiation, remained stable during treatment, and then decreased to near-baseline levels after the end of treatment (Figure 3). The proportion of patients with serum potassium ≥6.0 or ≥5.5 mEq/L on two consecutive measurements was significantly higher in the esaxerenone group (20 [9%]) compared with placebo (5 [2%]) (P=0.002). Rates of increased serum potassium ≥6.0 or ≥5.5 mEq/L at two consecutive measurements in the esaxerenone group were higher in patients with baseline serum potassium ≥4.5 versus <4.5 mEq/L, and in those with a baseline eGFR <60 versus ≥60 ml/min per 1.73 m2 (Table 3). Ten (4%) and one (<1%) patient(s) in the esaxerenone and placebo groups, respectively, discontinued treatment due to hyperkalemia.
Figure 3.
Esaxerenone increased serum potassium levels over the first 2 weeks. These remained stable during treatment and then decreased to near-baseline levels after the end of treatment. Time course of serum potassium (A) and mean change from baseline in serum potassium (B). Data are shown as mean±SD.
The percent change in eGFR from baseline to the end of treatment in the esaxerenone group was significantly higher than that in the placebo group (−11% versus −1%; a treatment difference of geometric least-square mean ratio to placebo at end of treatment 0.90 [95% CI, 0.88 to 0.93]).The eGFR continued to decrease until week 24, then remained stable and recovered to a level similar to that of the placebo group at the post-treatment follow-up (Figure 4). In addition, coadministration of DPP-4 or SGLT2 inhibitors did not appear to influence the extent of change from baseline to the end of treatment in eGFR (Supplemental Table 4). In a post hoc analysis, 12 (5%) and five (2%) patients in the esaxerenone and placebo groups, respectively, discontinued treatment due to two consecutive ≥30% reductions in eGFR.
Figure 4.
In the esaxerenone group, eGFR decreased until week 24, then remained stable and recovered to a level similar to the placebo group at the post-treatment follow-up. Time course of eGFR values (A) and geometric mean percent change from baseline in eGFR (B).Data are shown as geometric mean±95% confidence intervals.
Discussion
In this study, administration of esaxerenone for up to 52 weeks was associated with a >30% reduction in the UACR in about 70% of patients with type 2 diabetes and a UACR of 45 to <300 mg/g creatinine receiving RAS inhibitors, and our results showed the UACR returned to <30 mg/g creatinine in about 22% of patients and there was a 76% reduction in hazard of transition to UACR ≥300 mg/g creatinine. In addition, the proportion of patients who progressed to UACR ≥300 mg/g creatinine was reduced in the esaxerenone group (1%) compared with placebo (7%).
These findings are likely to be clinically relevant because meta-analysis data have shown a >30% reduction in albuminuria (relative to control) is associated with a decrease in the risk of developing ESKD (13). In addition, a study investigating the relationship between treatment-related decreases in albuminuria and lower relative risk of end-stage kidney failure reported that a 30% reduction from baseline in albuminuria over a 1-year period reduced the risk of ESKD by 18% (HR, 0.82; 95% CI, 0.74 to 0.91) (32). Nearly a quarter of all patients had normalization of the UACR during treatment with esaxerenone in our study. Improvement of albuminuria to normal levels has been reported to delay eGFR decline and kidney disease progression, and decrease cardiovascular event risk compared with type 2 diabetes patients with unchanged albuminuria (8,10,33,34).
Early intervention strategies to delay the progression of albuminuria would be expected to have an important effect on life expectancy, quality of life, and health care expenditure in patients with diabetes (35). In this study, progression of albuminuria was suppressed from an early stage after the addition of esaxerenone to existing stable RAS inhibitor therapy. The UACR gradually decreased until 24 weeks of treatment and then reductions were sustained during continued therapy up to 52 weeks; results were consistent regardless of seasonal fluctuations. Furthermore, there was no strong correlation between changes in UACR and decrease in BP or eGFR, suggesting the change in UACR seen in the esaxerenone group may not be entirely due to the antihypertensive effect or eGFR reduction. Despite BP, eGFR, and serum potassium levels being similar between the esaxerenone group and placebo group at week 4 of follow-up, UACR was lower in the esaxerenone group than in the placebo group. This might indicate structural improvement; however, 4 weeks of follow-up were not sufficient to determine this change properly. Further long-term follow-up is required.
Moreover, coadministration of DPP-4 or SGLT2 inhibitors did not appear to significantly affect the extent of change from baseline to the end of treatment in UACR, BP, or eGFR, so these drugs were thought to have negligible effects on esaxerenone treatment.
During the first 24 weeks of treatment with esaxerenone, eGFR gradually declined, but there was no further decrease for the remainder of the study. At the end of treatment, the eGFR reduction rate was about 10% on average. The percentages of patients with a ≥30% reduction in eGFR on two consecutive occasions were only 5% in the esaxerenone group and 2% in the placebo group. Therefore, we considered these eGFR reductions were acceptable in clinical settings. A recent study showed that even a 30% increase in serum creatinine did not adversely affect cardiovascular and kidney outcomes with antihypertensive therapy (36). However, we observed a greater change in the esaxerenone group than in the placebo, and regular monitoring is important for managing treatment.
Increased serum potassium levels are a known side effect of mineralocorticoid receptor blockers. In this study, the incidence of increased serum potassium levels (≥5.5 mEq/L on two consecutive measurements or ≥6.0 mEq/L) was higher in the esaxerenone group than in the placebo group. In half of esaxerenone-treated patients with elevated serum potassium, levels decreased with continued esaxerenone administration, or after dose reduction, whereas in the remaining patients, levels returned to the normal range after treatment discontinuation. The proportion of esaxerenone-treated patients who discontinued treatment due to increased serum potassium was similar between this study and the phase 2b study (4% and 3%, respectively) (28). There was no identifiable pattern in the timing of serum potassium elevations during the study, but increases in serum potassium in both the esaxerenone and placebo groups occurred most often in subgroups with low baseline eGFR or high baseline potassium levels. These groups may therefore need to be monitored closely during esaxerenone therapy.
Our results showed UACR reduction was greater than that observed in the Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy study examining the effect of the nonsteroidal mineralocorticoid receptor blocker finerenone on albuminuria in patients with DKD, while the occurrence of hyperkalemia and hyperkalemia leading to discontinuation were similar (37). In the Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy study, the prespecified secondary outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10 mg/d groups, whereas incidences of hyperkalemia in the finerenone 7.5, 15, and 20 mg/d groups were 2%, 3%, and 2%, respectively (37). A long-term phase 3 study of finerenone (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], [38]) was recently completed and met its primary endpoint, and another long-term trial of finerenone is in progress (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease [FIGARO-DKD], NCT02545049).
Several limitations need to be taken into account when interpreting the findings of this study. The first is the study duration, because a 52-week evaluation period may be insufficient to fully determine the effects of esaxerenone, given that the rate of decrease in eGFR in patients with early DKD is slow. Second, the study population was entirely from Japan, potentially limiting the generalizability and external validity of the findings.
In conclusion, the results of this phase 3 study showed the addition of esaxerenone to existing RAS inhibitor therapy can significantly reduce UACR and, in some patients, lead to UACR remission and reduce the risk of albuminuria progression. Remission occurred across the study population, indicating that early intervention could positively affect early-stage DKD. Furthermore, initiating therapy at low doses and regular monitoring was important to ensure the safety of these patients.
Disclosures
K. Shikata has received grants and personal fees from Daiichi Sankyo Co., Ltd. M. Nangaku has received grants and personal fees from Daiichi Sankyo Co., Ltd. N. Kashihara has received personal fees and research funding from Daiichi Sankyo Co., Ltd. S. Ito has received grants and personal fees from Daiichi Sankyo Co., Ltd. T. Wada has received grants and personal fees from Daiichi Sankyo Co., Ltd. Y. Okuda and T. Sawanobori are employees of Daiichi Sankyo Co., Ltd.
Funding
This research was funded by Daiichi Sankyo Co., Ltd.
Supplementary Material
Acknowledgments
The authors would like to thank Ms. Nicola Ryan, of Edanz Evidence Generation, for providing medical writing services, which were funded by Daiichi Sankyo Co., Ltd.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
See related editorial, “Mineralocorticoid Receptor Antagonists for Diabetic Kidney Disease,” on pages 1696–1698.
Data Sharing Statement
Deidentified individual participant data and applicable supporting clinical trial documents, which include participant demographics, medical histories, vitals, laboratory test results, adverse events, concomitant medications, and final patient statements, may be available on request at https://vivli.org/. Data will be available for sharing after the treatment agent has received marketing approval and after the study results have been accepted for publication. Requests for data will be reviewed by the Independent Review Panel on the basis of the scientific merit of the research proposal and bound by the limitation of participants’ consent. Data requested must execute the Data Use Agreement, and access will be provided for 1 year after the request has been authorized. Requests should be made via the Vivli Platform, through which access to the data will be provided. In cases where clinical study data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical study participants. Access to data may be declined if there is a potential conflict of interest or competitive risk between Daiichi Sankyo Co., Ltd. and the requesting party.
Supplemental Material
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.06870520/-/DCSupplemental.
Supplemental Figure 1. Study design.
Supplemental Figure 2. Patient disposition.
Supplemental Figure 3. Time course indicating treatment difference in the urinary albumin-creatinine ratio (UACR) change from baseline between the esaxerenone and placebo groups.
Supplemental Figure 4. Kaplan–Meier curve for time to first transition to UACR ≥300 mg/g creatinine.
Supplemental Figure 5. Mean change from baseline in sitting systolic BP (A) and sitting diastolic BP (B).
Supplemental Figure 6. Scatter plot showing the relationship between changes in the urinary albumin-to-creatinine ratio (UACR) at the EOT and cumulative mean change in systolic BP (⊿systolic BP) (A) or diastolic BP (⊿diastolic BP) (B).
Supplemental Figure 7. Scatter plot showing the relationship between changes in the urinary albumin-to-creatinine ratio (UACR) at the EOT and cumulative mean change in eGFR up to each visit (⊿eGFR).
Supplemental Table 1. Schedule of study assessments.
Supplemental Table 2. Reasons for discontinuation.
Supplemental Table 3. Proportion of patients achieving remission at the end of treatment (defined as two consecutive UACR values <30 mg/g creatinine and ≥30% reduction in UACR from baseline) in patient subgroups.
Supplemental Table 4. Changes in UACR, BP, and eGFR from baseline to the end of treatment in patients according to presence or absence of concomitant treatment with DPP-4 or SGLT2 inhibitors.
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