The renoprotective effect of esaxerenone independent of blood pressure lowering: a post hoc mediation analysis of the ESAX-DN trial.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are recommended as first-line drugs for hypertension with diabetic nephropathy owing to their renoprotective effect; however, their effect beyond lowering blood pressure (BP) has not been confirmed. Recent studies have shown that aldosterone plays a key role in causing renal injury; therefore, it is likely that mineralocorticoid receptor (MR) blockers inhibit aldosterone-induced renal damage in different ways from ACE inhibitors and ARBs. Therefore, we investigated the mechanism of the effect of an MR blocker on reducing the urinary albumin-to-creatinine ratio (UACR) using data from a randomized, double-blind, placebo-controlled phase 3 study (ESAX-DN) of a new nonsteroidal MR blocker, esaxerenone. This post hoc analysis used a novel statistical method to quantitatively estimate the effect of esaxerenone on UACR reduction mediated, or not mediated, by changes in systolic BP (SBP) and/or estimated glomerular filtration rate (eGFR). The proportion of the mediated effect by SBP changes to the total effect on UACR reduction was 9.8-10.7%; the UACR was reduced to 0.903-0.911 times the baseline at the end of treatment through the SBP-related pathway and to 0.422-0.426 times the baseline through the non-SBP-related pathway. Even considering both SBP and eGFR simultaneously, the proportion of the mediated effect was 21.9-28.1%. These results confirm that esaxerenone has a direct UACR-lowering effect independent of BP lowering and that its magnitude is much larger than that of the BP-dependent effect. Thus, esaxerenone could be a UACR-reducing treatment option for patients with diabetic nephropathy.

Reduction in the magnitude of serum potassium elevation in combination therapy with esaxerenone (CS-3150) and sodium-glucose cotransporter 2 inhibitor in patients with diabetic kidney disease: Subanalysis of two phase III studies.

AIMS/INTRODUCTION: We evaluated the effect of co-administration of esaxerenone and a sodium-glucose cotransporter 2 (SGLT2) inhibitor on the magnitude of serum potassium elevation in Japanese patients with diabetic kidney disease. MATERIALS AND METHODS: We carried out a prespecified subanalysis of data from two phase III studies: a multicenter, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes and microalbuminuria (J308); and a multicenter, single-arm, open-label trial in patients with type 2 diabetes and macroalbuminuria (J309). Changes in serum potassium levels during the studies and other measures were evaluated according to SGLT2 inhibitor use. RESULTS: In both studies, time-course changes in serum potassium levels, and incidence rates of serum potassium elevation were lower in patients with co-administration of SGLT2 inhibitor in both the placebo and esaxerenone groups than those without the inhibitor. In contrast, time-course changes and mean percentage changes from baseline in urinary albumin-to-creatinine ratio, the proportion of patients with albuminuria remission and time-course changes in blood pressure did not change with or without SGLT2 inhibitor, whereas the albumin-to-creatinine ratio and blood pressure were reduced with esaxerenone. The blood glucose-lowering effect of SGLT2 inhibitor was not affected by esaxerenone. CONCLUSIONS: In Japanese patients with type 2 diabetes and albuminuria treated with esaxerenone, concomitant use of SGLT2 inhibitor reduced the magnitude of serum potassium elevation without any change of its antihypertensive and albuminuria-suppressing effects. Co-administration of esaxerenone and SGLT2 inhibitor might be a beneficial treatment option for patients with diabetic kidney disease.

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.

Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN): Phase 3 Randomized Controlled Clinical Trial.

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.

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial.

BACKGROUND AND OBJECTIVES: The progression of kidney disease in some patients with type 2 diabetes mellitus may not be adequately suppressed by renin-angiotensin system inhibitors. Esaxerenone (CS-3150) is a nonsteroidal mineralocorticoid receptor blocker that has shown kidney protective effects in preclinical studies, and it is a potential add-on therapy to treat diabetic kidney disease. This phase 2 study evaluated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes mellitus and microalbuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This multicenter, randomized, double-blind, placebo-controlled trial enrolled 365 hypertensive or normotensive patients with type 2 diabetes mellitus and microalbuminuria (urinary albumin-to-creatinine ratio ≥45 to <300 mg/g creatinine) treated with renin-angiotensin system inhibitor who had eGFR≥30 ml/min per 1.73 m2. Participants were randomized to receive 0.625, 1.25, 2.5, or 5 mg/d esaxerenone or placebo for 12 weeks. The primary end point was the change in urinary albumin-to-creatinine ratio from baseline to week 12 (with last observation carried forward). RESULTS: Esaxerenone treatment at 1.25, 2.5, and 5 mg/d significantly reduced urinary albumin-to-creatinine ratio by the end of treatment (38%, 50%, and 56%, respectively) compared with placebo (7%; all P<0.001). The urinary albumin-to-creatinine ratio remission rate (defined as urinary albumin-to-creatinine ratio <30 mg/g creatinine at the end of treatment and ≥30% decrease from baseline) was 21% in the 2.5- and 5-mg/d groups versus 3% for placebo (both P<0.05). Adverse events occurred slightly more frequently with esaxerenone versus placebo, but the frequencies of drug-related adverse events and discontinuation rates were similar in the placebo and the 0.625-, 1.25-, and 2.5-mg/d groups. Drug-related adverse events and treatment discontinuations were marginally higher in the 5-mg/d group. The most common drug-related adverse event was hyperkalemia, which was dose proportional. CONCLUSIONS: Adding esaxerenone at 1.25, 2.5, and 5 mg/d for 12 weeks to an ongoing renin-angiotensin system inhibitor significantly reduces urinary albumin-to-creatinine ratio in patients with type 2 diabetes mellitus and microalbuminuria.