Mineralocorticoid receptor signaling inhibits bladder cancer progression.

The biological or clinical significance of mineralocorticoid receptor (MR) in urothelial cancer remains largely unknown. The present study aimed to determine the functional role of MR in bladder cancer progression. In two of the human bladder cancer lines expressing MR, treatment with a natural MR ligand, aldosterone, significantly reduced cell proliferation and migration, which was restored by three MR antagonists clinically used, spironolactone (except colony formation of androgen receptor-positive cells cultured in the presence of androgens), eplerenone, and esaxerenone. Similarly, MR knockdown via shRNA virus infection resulted in significant increases in cell viability/migration, as well as colony formation, compared with control sublines. In addition, MR knockdown augmented the expression of ß-catenin, c-fos, and N-cadherin, and lowered that of E-cadherin and p53, indicating the induction of the cadherin switching. Immunohistochemistry in surgical specimens detected MR signals in 58 (92.1%; 36.5% weakly-positive/1+, 44.4% moderately-positive/2+, and 11.1% strongly-positive/3+) of 63 muscle-invasive bladder cancers, which was significantly lower than in adjacent non-neoplastic urothelial tissues (100%; 15.7% 1+, 37.3% 2+, and 47.1% 3+). Moreover, patients with MR-high (3+) tumor had a significantly lower risk of cancer-specific mortality (P=0.039). Multivariable analysis further showed that strong MR expression was an independent predictor of cancer-specific survival in patients with muscle-invasive bladder cancer (hazard ratio 0.117, P=0.039). These findings suggest that MR signaling functions as a tumor suppressor in urothelial carcinoma and prevents tumor growth. Accordingly, there is a possibility that the concurrent use of anti-mineralocorticoids, particularly eplerenone and esaxerenone, in patients with bladder cancer rather contributes to the promotion of disease progression.

Effect of esaxerenone on ischaemia and reperfusion injury in rat hearts.

OBJECTIVES: In myocardial infarction, the addition of mineralocorticoid receptor blockers to standard therapies, such as angiotensin-converting enzyme inhibitors or beta-blockers, reportedly reduces mortality and cardiac events. We investigated whether the non-steroidal mineralocorticoid receptor blocker esaxerenone has cardioprotective effects and its protective mechanisms. METHODS: Isolated rat hearts were Langendorff-perfused (constant pressure, 80 mmHg) with oxygenated Krebs-Henseleit bicarbonate buffer and reperfused for 60 min; afterwards, recovery of function (left ventricular pressure, measured with an intraventricular balloon) and myocardial injury were measured. In a preliminary study, we determined the optimal concentration of esaxerenone required for myocardial protection. Next, esaxerenone was administered in the pre- and post-ischaemic phases to determine the optimal timing of administration. In addition, we assessed coronary flow response to acetylcholine with and without esaxerenone. We examined whether esaxerenone-induced cardioprotection was prevented by targeting putative components in the preconditioning manner (the mitochondrial ATP-sensitive potassium [KATP] channel). RESULTS: Myocardial protection by esaxerenone was observed when esaxerenone was administered before ischaemia but not after ischaemia. The coronary flow response to acetylcholine was significantly better in the esaxerenone group than in the control group. The cardioprotective effect of esaxerenone was eliminated by the mitochondrial KATP channel blocker, 5-hydroxy decanoate. CONCLUSIONS: This study confirmed the myocardial protective effect of the pre-ischaemic administration of esaxerenone. Esaxerenone may contribute to coronary endothelial protection and exert pharmacological preconditioning via the mitochondrial KATP channel.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetes Mellitus Undergoing Treatment with Sodium-Glucose Cotransporter 2 Inhibitors (EAGLE-DH).

INTRODUCTION: The EAGLE-DH study assessed the efficacy and safety of esaxerenone in hypertensive patients with diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors. METHODS: In this multicenter, open-label, prospective, interventional study, esaxerenone was started at 1.25 or 2.5 mg/day and could be gradually increased to 5 mg/day on the basis of blood pressure (BP) and serum potassium levels. Oral hypoglycemic or antihypertensive medications prior to obtaining consent was continued. Data were evaluated in the total population and creatinine-based estimated glomerular filtration rate (eGFR) subcohorts (eGFR ≥ 60 mL/min/1.73 m2 [G1-G2 subcohort] and 30 to < 60 mL/min/1.73 m2 [G3 subcohort]). RESULTS: In total, 93 patients were evaluated (G1-G2, n = 49; G3, n = 44). Morning home systolic/diastolic BP values (SBP/DBP) were significantly reduced from baseline to week 12 (- 11.8 ± 10.8/- 5.1 ± 6.3 mmHg, both P < 0.001) and week 24 (- 12.9 ± 10.5/- 5.7 ± 6.3 mmHg, both P < 0.001). Similar results were observed in both eGFR subcohorts. The urinary albumin-to-creatinine ratio significantly decreased from baseline to week 24 in the total population (geometric percentage change, - 49.1%, P < 0.001) and in both eGFR subcohorts. The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 45.2% and 12.9%, respectively; most were mild or moderate. Serum potassium levels increased over the first 2 weeks of esaxerenone treatment, gradually decreased by week 12, and remained constant to week 24. One patient in the G1-G2 subcohort had serum potassium levels ≥ 5.5 mEq/L. No patients had serum potassium ≥ 6.0 mEq/L. CONCLUSION: Esaxerenone effectively lowered BP, was safe, and showed renoprotective effects in hypertensive patients with diabetes mellitus receiving treatment with SGLT2 inhibitors. Esaxerenone and SGLT2 inhibitors did not interfere with either drug's efficacy and may reduce the frequency of serum potassium elevations, suggesting they are a compatible combination. CLINICAL TRIAL REGISTRATION: jRCTs031200273.

Protective role of mineralocorticoid receptor signaling in urothelial tumorigenesis.

The expression status of mineralocorticoid receptor (MR) and its biological significance in human urothelial carcinoma remain unknown. The present study aimed to determine the functional role of MR in the development of urothelial cancer. In human normal urothelial SVHUC cells with exposure to a chemical carcinogen 3-methylcholanthrene (MCA), we assessed the effects of a natural MR ligand, aldosterone, and 3 MR antagonists, including spironolactone, eplerenone, and esaxerenone, as well as knockdown of MR via shRNA virus infection, on their neoplastic/malignant transformation. The in vitro system with carcinogen challenge showed that aldosterone and anti-mineralocorticoids significantly prevented and promoted, respectively, the neoplastic transformation of SVHUC cells. Similarly, MR knockdown in SVHUC cells considerably induced MCA-mediated neoplastic transformation, compared with a control subline. In addition, MR knockdown or antagonist treatment resulted in increases in the expression of ß-catenin, c-Fos, and N-cadherin, and a decrease in that of E-cadherin. Meanwhile, spironolactone, which is known to possess anti-androgenic activity, rather suppressed the neoplastic transformation of a SVHUC subline stably expressing wild-type androgen receptor, indicating its dominant effect via the androgen receptor pathway. Immunohistochemistry in surgical specimens detected MR signals in 77 (98.7%; 23.1% weak/1+, 42.3% moderate/2+, and 33.3% strong/3+) of 78 non-invasive bladder tumors, which was significantly (P<0.001) lower than in adjacent non-neoplastic urothelial tissues (100%; 20.5% 2+ and 79.5% 3+). Moreover, the risks for disease recurrence after transurethral surgery were marginally lower in female patients with MR-high (2+/3+) tumor (P=0.068) and significantly lower in all patients with MR-high/glucocorticoid receptor-high tumor (P=0.025), compared with respective controls. These findings suggest that MR signaling functions as a suppressor for urothelial tumorigenesis.

Factors Associated with the Antihypertensive Effect of Esaxerenone and Serum Potassium Elevation: A Pooled Analysis of Seven Phase III Studies.

INTRODUCTION: This study investigated factors associated with the antihypertensive effects of esaxerenone and the incidence of serum potassium elevation in patients with hypertension. METHODS: Using pooled data from seven phase III studies, the study analyzed factors associated with changes in office systolic (SBP) and diastolic (DBP) blood pressure from baseline to 12 weeks, and factors associated with incidence of serum potassium levels ≥ 5.5 mEq/L in esaxerenone-treated patients. RESULTS: Overall, 1466 and 1472 patients were included in the full analysis and safety analysis sets, respectively. Male sex (4.02/2.40 mmHg), weight ≥ 78.4 kg (4.62/2.09 mmHg), hypertension duration ≥ 10 years (2.66/1.71 mmHg), prior antihypertensive treatment (2.38/1.40 mmHg), plasma aldosterone concentration ≥ 120 pg/mL (1.66/1.17 mmHg), urinary albumin-to-creatinine ratio (UACR) ≥ 300 mg/gCr (8.94/4.85 mmHg) or 30-299 mg/gCr (5.17/4.15 mmHg), and smoking (2.62/1.27 mmHg) were associated with mean changes in SBP and DBP. Fasting blood glucose ≥ 126 mg/dL (- 2.73 mmHg) was associated with the mean change in SBP only, and older age (65-74 years, - 2.12 mmHg; and ≥ 75 years, - 3.06 mmHg) with mean change in DBP only. Factors significantly associated with incidence of serum potassium levels ≥ 5.5 mEq/L were higher baseline serum potassium (≥ 4.5 mEq/L, odds ratio [OR] 6.702); lower estimated glomerular filtration rate (≥ 90 mL/min/1.73 m2, OR 0.148; 60-89 mL/min/1.73 m2, OR 0.331 vs 30-59 mL/min/1.73 m2, respectively); higher UACR (30-299 mg/gCr, OR 7.317); higher DBP (≥ 100 mmHg, OR 3.248); and grade I hypertension (OR 2.168). CONCLUSION: Esaxerenone is effective in patients with a broad range of backgrounds, though some factors may predict increased benefit. Regarding elevated serum potassium, careful therapeutic management is recommended for patients with higher baseline serum potassium and reduced renal function. CLINICAL TRIAL REGISTRATION: UMIN000047026.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study.

INTRODUCTION: Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. METHODS: In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. RESULTS: In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m2. CONCLUSION: Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction. CLINICAL TRIAL REGISTRATION: jRCTs06119002.

The Time to Reconsider Mineralocorticoid Receptor Blocking Strategy: Arrival of Nonsteroidal Mineralocorticoid Receptor Blockers.

PURPOSE OF REVIEW: The study aims to verify the advantages of nonsteroidal mineralocorticoid receptor blockers (MRBs) in the management of hypertension and cardiovascular and renal diseases, comparing with conventional MRBs. RECENT FINDINGS: Based on the unique structures, the nonsteroidal MRBs have higher selectivity for mineralocorticoid receptors (MRs) and show no agonist activity for major steroid hormone receptors in contrast to steroidal MRBs. Today, there are two nonsteroidal MRBs, esaxerenone and finerenone, which completed phase 3 clinical trials. Series of clinical trials have shown that both agents achieve similar MR blockade with smaller doses as compared with steroidal MRBs, but have no off-target side effect such as gynecomastia. Esaxerenone has persistent blood pressure-lowering effects in various hypertensive populations, including essential hypertension and those with diabetes and/or chronic kidney disease, while finerenone has demonstrated reduction of the cardiovascular risk rather than blood pressure in patients with diabetes and chronic kidney disease. Nonsteroidal MRBs are a more refined agent which contributes to appropriate MR blocking with minimized unpleasant adverse effects.

Effects of mineralocorticoid receptor antagonists on sex hormones and body composition in patients with primary aldosteronism.

Mineralocorticoid receptor antagonists are frequently used for the treatment of primary aldosteronism. Steroidal mineralocorticoid receptor antagonists may have antagonistic actions on androgen receptors, agonistic actions on progesterone receptors, and antagonistic actions on mineralocorticoid receptors. Because anti-androgen effects may cause body fat accumulation and skeletal muscle atrophy, there are concerns that this drug may have adverse effects on body composition. Therefore, in this randomized prospective study, we compared the adverse effects of spironolactone, a steroidal mineralocorticoid receptor antagonist, and esaxerenone, a nonsteroidal mineralocorticoid receptor antagonist, on sex hormone levels and body composition in patients with primary aldosteronism without severe renal dysfunction. The serum concentration of free testosterone was significantly higher in the spironolactone group than in the esaxerenone group in both males and females. However, the levels of estradiol, progesterone, luteinizing hormone, and follicle stimulating hormone did not significantly increase. Changes in body fat percentage and muscle mass rate were not significantly different between the two groups. No patient showed a serum potassium level ≥6.0 mEq/L; however, serum potassium levels were significantly higher in the spironolactone group than in the esaxerenone group. These data indicate that spironolactone may have antagonistic effects on androgen receptors. Esaxerenone did not show any apparent adverse effects, suggesting that it can be safely used in patients with primary aldosteronism.

Efficacy and safety of esaxerenone (CS-3150) in Japanese patients with type 2 diabetes and macroalbuminuria: a multicenter, single-arm, open-label phase III study.

BACKGROUND: Esaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine). METHODS: We conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and treated with a renin-angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K+) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K+ increase, and change in eGFR from baseline. RESULTS: UACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K+ levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K+ values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was - 8.3 mL/min/1.73 m2 at week 24. CONCLUSIONS: Esaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR < 300 mg/g creatinine. CLINICAL TRIAL REGISTRATION: JapicCTI-173696.

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism.

Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] -17.7 [-20.6, -14.7] and -9.5 [-11.7, -7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K+ increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.