Amiloride: revisiting an old drug for resistant hypertension

Resistant hypertension (RH) remains a major clinical challenge, defined as uncontrolled blood pressure (BP) despite the use of 3 antihypertensive agents, including a renin-angiotensin system inhibitor, a calcium channel blocker, and a diuretic, or the need for 4 or more agents. Spironolactone has been considered the most effective fourth-line therapy, supported by the PATHWAY-2 trial, but its real-world use is limited by adverse effects such as gynecomastia, menstrual irregularities, and hyperkalemia. Therefore, there was a clinical need for alternative agents, and thus the use of amiloride, an epithelial sodium channel (ENaC) inhibitor and potassium-sparing diuretic, has been proposed. Data from PATHWAY-2 suggested amiloride's comparable BP-lowering efficacy, though based only on an open-label extension. Recently, the SPironolactone versus Amiloride for REsistant hypertension (SPARE) trial provided the first randomized evidence directly comparing the 2 agents. In 118 patients with RH inadequately controlled on fixed-dose triple therapy, participants were randomized to spironolactone 12-25 mg or amiloride 5-10 mg for 12 weeks. Mean reductions in home systolic blood pressure (SBP) were -14.7 mmHg with spironolactone and -13.6 mmHg with amiloride, meeting the prespecified non-inferiority margin. Safety profiles were favorable, with only one discontinuation due to hyperkalemia in the amiloride group and no reports of gynecomastia. Subgroup analyses suggested greater efficacy of amiloride in patients with higher body mass index and lower aldosterone-renin ratios, highlighting a potentially distinct mechanism of action. Unlike spironolactone, whose efficacy correlated with aldosterone activity, amiloride showed consistent SBP reduction across renin and aldosterone levels. Beyond its renal ENaC inhibition, amiloride may also modulate vascular biology. In addition to its inhibition of renal ENaCs, amiloride may also have an impact on vascular biology. Experimental studies indicate that ENaC is present in endothelial cells, where its activation can lead to reduced nitric oxide release, increased oxidative stress, endothelial stiffness, and vascular fibrosis. Amiloride may consistently lower BP across a wide range of renin-aldosterone activity by improving endothelial function through the inhibition of ENaC, as well as by decreasing intravascular volume. The findings from the SPARE trial suggest that amiloride may be a viable alternative to spironolactone for RH, particularly in patients who are intolerant to mineralocorticoid receptor antagonists. While spironolactone remains the preferred option due to its established role in blocking systemic aldosterone activation and proven cardiovascular benefits, amiloride can provide a practical and well-tolerated alternative.