Nonsteroidal Mineralocorticoid Receptor Antagonists
The observation that the use of currently available steroidal MRAs in daily clinical practice is associated with intolerable side effects, such as with an increased risk of hyperkalaemia, has led to the discovery and development of nonsteroidal MRAs with the aim to maintain the potent and selective inhibition of the mineralocorticoid receptor with a more favourable safety profile.[21,22] Agents that belong to the novel class of nonsteroidal MRAs and have progressed into an advanced stage of clinical development are the following: finerenone, esaxerenone and KBP-5074. Differences in clinical efficacy among nonsteroidal MRAs, such as BP-lowering action, appear to exist, but the superiority of one agent over the other remains unclear in the absence of trials to provide direct head-to-head comparisons.[21,22]
On the basis of firm evidence from the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) trial, the U.S. Food and Drug Administration recently approved finerenone for use in daily clinical practice with the indication of cardiorenal protection in patients with CKD and type 2 diabetes. Whether this recently approved nonsteroidal MRA is also effective in improving BP control in the subset of patients with uncontrolled or resistant hypertension and CKD remains unanswered. In the FIDELIO-DKD trial, finerenone provoked a placebo-subtracted reduction of 2–3 mmHg in office SBP. This modest BP-lowering effect contrasts with the reduction of 11–12 mmHg in unattended automated office SBP seen with spironolactone over the course of the AMBER trial. Whether finerenone is a safer substitute for spironolactone in the subgroup of patients with moderate-to-advanced CKD and uncontrolled resistant hypertension warrants further investigation.
On the basis of evidence from a large phase 3 trial demonstrating a potent BP-lowering action of esaxerenone, this novel selective nonsteroidal MRA received regulatory approval in Japan for the treatment of essential hypertension. The safety and BP-lowering efficacy of esaxerenone was investigated in two multicentre, open-label, nonrandomized, dose-escalation studies that included patients with hypertension and moderate kidney dysfunction (eGFR ≥30 and <60 ml/min/1.73 m2). Esaxerenone was administered at an initial dose of 1.25 mg/day that was uptitrated to 2.5 and then 5 mg/day. Over a follow-up period of 12 weeks, monotherapy with esaxerenone was accompanied by a reduction of 18.5/8.8 mmHg in sitting office BP. When esaxerenone was administered as add-on therapy to patients already treated with an ACEI or an ARB, a similar reduction of 17.8/8.1 mmHg in sitting office BP was observed. Hyperkalaemia (defined as serum potassium ≥5.5 mEq/l) was not seen with monotherapy, but occurred in seven out of 58 patients (12.1%) who received add-on therapy with esaxerenone.
In the ESAX-DN [Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria] trial, 455 patients with type 2 diabetes and high albuminuria (urinary albumin-to-creatinine ratio of 45 to <300 mg/g and eGFR ≥30 ml/min/1.73 m2) receiving background treatment with an ACEI or an ARB were randomized to esaxerenone (1.25–2.5 mg/day) or placebo over 52 weeks of follow-up. As compared with placebo, esaxerenone significantly increased the proportion of patients who achieved remission of albuminuria (between-group difference: 18%; 95% CI: 12.0--25.0). The BP-lowering efficacy of esaxerenone in patients with mild-to-moderate CKD was also confirmed. Over the course of the ESAX-DN trial, a median reduction of 10 mmHg in sitting office SBP was observed in the esaxerenone group, but not in the placebo group. As expected, hyperkalaemia occurred more commonly with active treatment than with placebo, but these events were easily manageable either with reduction of the dose of esaxerenone or with transient drug discontinuation. A subsequent single-arm interventional study showed that therapy with esaxerenone was associated with a 54.6% reduction in urinary albumin-to-creatinine ratio in 56 patients with type 2 diabetes and very high albuminuria. Whether this positive benefit/risk ratio of esaxerenone persists in patients with more advanced CKD requires investigation in future trials.
KBP-5074 is an investigational nonsteroidal MRA with higher selectivity and stronger binding affinity to the mineralocorticoid receptor as compared with spironolactone and eplerenone.[29,30] Pharmacokinetic studies showed that KBP-5074 exhibits a prolonged plasma half-live of nearly 60 h that is suggestive of a potent and sustained haemodynamic effect. BLOCK-CKD (Study of KBP-5074 in Subjects With Uncontrolled Hypertension and Advanced Chronic Kidney Disease) was a phase 2b trial aiming to explore the safety and BP-lowering efficacy of this agent in 162 patients with stage 3b/4 CKD and inadequately controlled hypertension. Over 84 days of follow-up, as compared with placebo, the addition of KBP-5074 0.25 mg/day to standard treatment provoked a mean change of -7.0 mmHg in office SBP. The placebo-subtracted change in office SBP provoked by KBP-5074 0.50 mg/day was -10.2 mmHg. The incidence of hyperkalaemia was comparable between active-treatment and placebo group. On the basis of these positive preliminary data, a phase 3 trial with a randomized withdrawal period (NCT04968184) has been designed to explore the safety, efficacy and durability of BP-lowering action of KBP-5074 in 600 patients with stage 3b/4 CKD and poorly controlled hypertension.
Curr Opin Nephrol Hypertens. 2022;31(4):374-379. © 2022 Lippincott Williams & Wilkins