Hypertension
Corey Diamond, PharmD
Patients with resistant hypertension often fail to achieve BP control despite using multiple antihypertensive agents. Clinicians commonly prescribe spironolactone in this setting, but concerns about adverse effects, including gynecomastia and hyperkalemia, have led to interest in alternatives. Amiloride, a potassium-sparing diuretic with a different mechanism of action, offers one such option.
In a multicenter study published in JAMA in May 2025, Lee and colleagues compared spironolactone and amiloride in patients with resistant hypertension. The study found that both medications lowered BP to a similar degree for patients with resistant hypertension, with minor differences in safety outcomes.
The trial showed nearly identical efficacy across systolic and diastolic measurements, with comparable proportions of patients reaching target values.
Results
The study enrolled and randomized 114 patients: 56 to amiloride and 58 to spironolactone. Baseline characteristics remained well-balanced between groups.
At week 12, both groups demonstrated a mean reduction of 14 mm Hg in home systolic BP. Morning and evening systolic and diastolic pressures also declined to similar extents. Investigators reported no statistically significant differences in primary or secondary BP endpoints between the groups.
In terms of BP targets, 39.3% of patients in the amiloride group and 34.5% of patients in the spironolactone group achieved a home BP of less than 130/80 mm Hg. Office BP results showed a similar trend, with approximately 36% in both groups reaching guideline-recommended thresholds. These proportions did not differ meaningfully.
The researchers observed a higher incidence of hyperkalemia in the amiloride group. At week 4, 16.1% of patients in the amiloride group had serum potassium levels of 5.0 mmol/L or greater, compared to 6.9% in the spironolactone group.
Despite this, only one patient discontinued therapy due to hyperkalemia. One patient in the spironolactone group developed AKI, which resolved after discontinuation. No patients in either group reported gynecomastia, and the trial recorded only one serious adverse event overall.
Study design
The investigators conducted a randomized, open-label, controlled trial across multiple centers in South Korea. They screened adults between 19 and 75 years old who met strict criteria for resistant hypertension. To qualify, each patient needed a documented systolic BP of 130 mm Hg or higher despite taking at least three antihypertensive medications, including a diuretic. The team required confirmation through 24-hour ambulatory monitoring or a series of standardized home measurements.
Participants who met inclusion criteria received random assignments to spironolactone or amiloride. The trial followed them over 12 weeks. Investigators allowed dose titrations at weeks 4 and 8 based on BP response and lab values. They excluded individuals with secondary hypertension, advanced kidney disease, uncontrolled cardiovascular conditions, arrhythmias, liver dysfunction, recent use of study medications, or pregnancy. They also excluded patients with recent drug or alcohol dependence, poor adherence potential, or contraindications to the study drugs.
Investigators measured BP at home and in a clinic setting using validated protocols. Each patient performed two morning and two evening home measurements across multiple days, yielding robust averages. Investigators collected lab samples at baseline and at follow-up visits to assess serum potassium, renal function, and other metabolic parameters.
The primary endpoint assessed change in average home systolic BP from baseline to week 12. Secondary outcomes included changes in diastolic pressure, rates of target BP attainment, frequency of adverse events, drug adherence, and dose changes over time.
Discussion
Investigators saw no major difference in drug effectiveness, suggesting that both agents offer valid therapeutic options in this population.
“This study reinforces that clinicians have more than one effective option for managing resistant hypertension,” said the authors, “When spironolactone isn’t the right fit, amiloride can step in as a strong alternative.”
The findings offer a direct comparison of two potassium-sparing therapies and clarify their roles in a setting where evidence has remained limited. The data support the selective use of amiloride when spironolactone is contraindicated or poorly tolerated, with the understanding that serum potassium monitoring remains essential. ■