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

Abstract

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.

Nighttime home blood pressure lowering effect of esaxerenone in patients with uncontrolled nocturnal hypertension: the EARLY-NH study

“…Because esaxerenone continuously reduces UACR up to 6 months after administration, followed by a steady state [ 17 ], further UACR reduction can be expected with long-term administration. Although part of this UACR-lowering effect is due to the reduction in circulating and renal blood flow by lowering BP [ 19 ], recent statistical medication analysis has shown that direct MR inhibition, independent of the antihypertensive effect, reduces UACR [ 30 ].…”

Rationale and design of a multicenter randomized study comparing the efficacy and safety of esaxerenone versus trichlormethiazide in patients with uncontrolled essential hypertension: EXCITE‐HT study

“…The present study will also examine the UACR‐lowering effect as well as safety, including effects on glucose, lipid, and UA metabolism. Esaxerenone and thiazide diuretics have a similar mechanism for UACR‐lowering effects, whereby circulating and renal blood flow are reduced by lowering BP; however, esaxerenone is suggested to have another mechanism that involves direct inhibitory action against mineralocorticoid receptors in the kidney 40 . Therefore, a comparison of the UACR‐lowering effect may also provide insight into this different mechanism of UACR reduction.…”

Mineralocorticoid Receptor Antagonists for Preventing Chronic Kidney Disease Progression: Current Evidence and Future Challenges

“…In the esaxerenone group, there was a significant reduction in blood pressure from baseline (−10/−5 mmHg) [163]. A post-hoc analysis of the study indicated that around 10% of the UACR-lowering effect of esaxerenone could be mediated by the reduction in systolic blood pressure [164].…”