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

Abstract

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 m 2 . 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. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-022-02294-z.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Left Ventricular Hypertrophy (ESES-LVH) Study: A Multicenter, Open-Label, Prospective, Interventional Study

“…Similar significant reductions in the total population and both subcohorts were observed in bedtime home and office SBP/DBP, indicating that esaxerenone would exhibit a consistent antihypertensive effect in this patient population and that these effects would be independent of concomitant use of RASis or CCBs. The reduction in morning home SBP/DBP in this study was comparable to the EX-DKD study in hypertensive patients with diabetic kidney disease treated with a RASi alone or a RASi plus CCB (− 11.6/− 5.2 mmHg) [ 30 ]. In addition, the change in office SBP/DBP in this study (− 15.1/ − 6.5 mmHg) was also similar to that shown in phase 3 studies of esaxerenone in RASi-treated hypertensive patients with moderate renal dysfunction (− 17.8/ − 8.1 mmHg) [ 25 ] and with type 2 diabetes associated with microalbuminuria (− 13.7/− 6.2 mmHg) [ 26 ].…”

“…Esaxerenone, a selective nonsteroidal MRB, has favorable antihypertensive effects in patients with hypertension with various background characteristics [ 22 – 30 ] and has good renoprotective effects including reduction and remission of albuminuria in hypertensive patients with diabetic kidney disease [ 25 , 26 , 28 – 31 ]. Esaxerenone is also expected to exert cardioprotective effects in terms of regression of cardiac hypertrophy via its mechanism of action [ 32 ].…”

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

“…However, previous phase 3 clinical trials have demonstrated that esaxerenone administered as a second‐line agent exerted a reliable office BP‐lowering effect in uncontrolled hypertensive patients with a variety of backgrounds who have insufficient responses to first‐line antihypertensive agents 12–19 . Furthermore, the recent post‐marketing clinical studies have also shown that esaxerenone administered as a second‐ or third‐line agent reduced morning home and nighttime BPs in patients with uncontrolled hypertension, achieving 24‐hour BP control 20,21 . These phase 3 and post‐marketing studies have confirmed not only the antihypertensive effect, but also the organ‐protective effect of esaxerenone, including albuminuria, NT‐proBNP, and cardio‐ankle vascular index‐lowering effects 13,15,16,18–21,24 .…”

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

“…While not reaching statistical significance in all analyses, patients with UACR < 30 mg/gCr tended to experience a stronger antihypertensive effect that reached our definition of clinical significance, compared with patients with higher UACR. Esaxerenone has previously been reported to improve UACR [ 12 , 13 , 15 , 16 , 26 ]; this may indicate that the use of esaxerenone during the early stages of diabetes (i.e., in the absence of albuminuria) can provide a stronger antihypertensive effect while simultaneously delaying the transition to microalbuminuria [ 27 ]. In addition, this study revealed that the antihypertensive effect of esaxerenone was constant irrespective of the presence or absence of diabetes or the hemoglobin A1c levels, and was partially enhanced at higher fasting glucose levels in office SBP in the overall population.…”