Esaxerenone as good as eplerenone in management of essential hypertension

Esaxerenone appears to be safe and effective in the treatment of patients with essential hypertension, exerting noninferior blood pressure (BP)-lowering effects as compared with eplerenone, according to the results of the phase III ESAX-HTN study.

“The currently available mineralocorticoid receptor (MR) blockers spironolactone and eplerenone are often recommended in combination with other antihypertensives to treat resistant hypertension,” although their safety profiles make them unsuitable for patients with comorbidities, for whom good BP control is important, the investigators said.

In ESAX-HTN, the investigators evaluated the risk-benefit profile of the novel nonsteroidal selective MR blocker esaxerenone for use as an alternative therapy in hypertensive patients with relevant comorbidities.

The analysis included 998 patients (mean age, 55.5 years; 72.2 percent male) with mean sitting systolic/diastolic BP (SBP/DBP) of 155.3/98.1 mm Hg at baseline. Of these, 330 and 337 patients were randomly assigned to treatment with esaxerenone 2.5 or 5 mg, respectively, and the remaining 331 to eplerenone 50 mg. The drugs were taken orally once daily for 12 weeks.

At treatment conclusion, esaxerenone 5 mg yielded significantly greater reductions in the primary endpoint of sitting SBP/DBP compared with the 2.5-mg dose (mean differences, −3.4 mm Hg for SBP; p=0.0001 and −1.7 mm Hg for DBP; p=0.0011) and with eplerenone (mean differences, −4.6 mm Hg for SBP and −2.1 mm Hg for DBP; p-both<0.0001). Results for 24-hour BP showed a similar pattern. [Hypertension 2020;75:51-58]

Target sitting BP (<140/90 mm Hg) was achieved by 31.5 of patients in the esaxerenone 2.5-mg arm, 41.2 percent in the 5-mg arm and 27.5 percent in the eplerenone 50-mg arm.

“Esaxerenone dose-dependently reduced sitting BP in all subgroups [examined]. Decreases in sitting BP were numerically greater in females, and in patients aged ≥65 years, with low body mass index (<25 kg/m²), high baseline sitting SBP (≥160 mm Hg), and lower baseline levels of plasma aldosterone concentration, plasma renin activity and triglycerides,” the investigators noted.

The BP-lowering advantage observed with the experimental drug was independent of hypertension grade and glycosylated haemoglobin level, they added. “Diabetic comorbidities did not influence the BP reductions achieved with esaxerenone 2.5 mg/day, but there was a trend for greater reductions [at the higher dose] in their presence.”

In terms of safety, there were no striking differences in the incidence of adverse events (AEs). All AEs were mild or moderate in severity, having resolved or decreased in severity over time or at treatment conclusion. Treatment-related AEs were documented in 7.6 percent in the esaxerenone 2.5-mg arm, 9.2 percent in the 5-mg arm, and 4.8 percent in the eplerenone arm. Elevations in serum levels of potassium were the most frequently reported drug-related AE, with the rates slightly higher in the esaxerenone arms (1.8 percent with 2.5 mg, 2.1 percent with 5 mg, and 0.6 percent with eplerenone).

“This was the first large-scale, randomized, comparator-controlled phase III study to evaluate the antihypertensive effect of esaxerenone in patients with essential hypertension,” according to the investigators. “The magnitude and 24-hour sustainability of the BP reductions seen in this study suggest that [the drug] can be used as an antihypertensive agent in clinical practice, even as monotherapy.”

The present ESAX-HTN data and the results of previous studies investigating esaxerenone in patients with diabetes and albuminuria, in combination with other BP-lowering medications, and in populations with renal impairment (which will be available soon) are expected to further the clinical positioning of the drug as a nonsteroidal specific MR blocker, the investigators added. [Clin J Am Soc Nephrol 2019;14:1161-1172; Hypertens Res 2019;42:1572-1581; Hypertens Res 2019;doi:10.1038/s41440-019-0314-7]