Addition of Sacubitril/Valsartan to Mineralocorticoid Receptor Antagonist Therapy in Primary Aldosteronism: Effects on Plasma Aldosterone Concentration and Plasma Renin Activity

Abstract

In the pharmacologic treatment of primary aldosteronism (PA), titration of mineralocorticoid receptor antagonist (MRA) dosing is necessary to reverse the renin suppression caused by high aldosterone levels. However, we often encounter cases in which the plasma renin activity (PRA) does not achieve the target level, even with the maximum dose of MRA. In this setting, sacubitril/valsartan, a combination of a neprilysin inhibitor and an angiotensin II type 1 receptor blocker that is approved for use as adjunctive therapy with an MRA, has been reported to inhibit aldosterone secretion both in vitro and in vivo. If sacubitril/valsartan proves to be effective in this context, it may offer a promising treatment for PA. However, there are few reports on the use of sacubitril/valsartan in this disease. We used add-on sacubitril/valsartan in three patients with PA, in whom blood pressure was insufficiently reduced and PRA remained suppressed despite administering the maximum dose of MRA. With the addition of sacubitril/valsartan, the decrease in plasma aldosterone concentration (PAC) was more marked than the increase in PRA. Because MRAs do not suppress aldosterone production but instead act by blocking mineralocorticoid receptors, use of these agents actually promotes the renin-angiotensin system and leads to increased PAC resulting from positive feedback. The pathological significance of the phenomenon whereby PAC increases with MRA administration but decreases with the addition of sacubitril/valsartan is unclear. In PA, more effective treatment may be possible by suppressing aldosterone with sacubitril/valsartan and blocking the action of aldosterone with MRAs.

Keywords: Aldosterone; Hypertension; Mineralocorticoid receptor antagonists; Primary aldosteronism; Renin; Sacubitril/valsartan.

Figure 1

Case 1 involved a patient with primary aldosteronism likely caused by an aldosterone-producing adenoma (calcium channel blocker → sacubitril/valsartan). The patient was on amlodipine, with insufficient reduction in BP. Therefore, esaxerenone was added, although BP still did not decrease sufficiently, and the PAC increased. Amlodipine was subsequently changed to sacubitril/valsartan; PRA temporarily increased, and the PAC gradually decreased. PAC: plasma aldosterone concentration; PRA: plasma renin activity; ARR: aldosterone-to-renin ratio; SBP: systolic blood pressure; DBP: diastolic blood pressure; PR: pulse rate; bpm: beats per minute.

Figure 2

Case 2 involved a patient with primary aldosteronism likely caused by idiopathic hyperaldosteronism (calcium channel blocker → sacubitril/valsartan). Although the addition of esaxerenone led to an increased PAC, PRA did not sufficiently increase. About 3 years after esaxerenone was added, the PAC gradually decreased. After switching amlodipine to sacubitril/valsartan, the PAC and ARR decreased slightly. *PAC values measured by radioimmunoassay prior to March 2021 have been converted to values consistent with the use of CLEIA to reflect changes in the standard assay used to measure PAC [19]. PAC: plasma aldosterone concentration; PRA: plasma renin activity; ARR: aldosterone-to-renin ratio; CLEIA: chemiluminescent enzyme immunoassay.

Figure 3

Case 3 involved a patient with primary aldosteronism likely caused by idiopathic hyperaldosteronism (spironolactone → sacubitril/valsartan). Although eplerenone was changed to esaxerenone, PRA did not exceed 1.0 ng/mL/h. After the patient temporarily self-discontinued treatment, the PAC (which had been elevated with mineralocorticoid receptor antagonist decreased, and PRA was again suppressed as a result of primary aldosteronism. After the medication regimen was resumed, sacubitril/valsartan was added. Because PRA markedly increased and the PAC decreased, spironolactone was discontinued, and sacubitril/valsartan was increased to the maximum dose. Finally, the PAC and ARR decreased, and PRA remained above 1.0 ng/mL/h. PAC: plasma aldosterone concentration; PRA: plasma renin activity; ARR: aldosterone-to-renin ratio.

Figure 4

Schema of the renin-angiotensin-aldosterone system and sacubitril/valsartan. As valsartan blocks angiotensin II type 1 receptors and sacubitril exerts a natriuretic peptide-mediated effect on the adrenal glands, the combination of sacubitril/valsartan directly suppresses aldosterone production and secondarily suppresses the mineralocorticoid receptor-mediated effect. Because the mineralocorticoid receptor is blocked by administration of an MRA, however, positive feedback activates the RAAS and stimulates aldosterone production. ACE: angiotensin-converting enzyme; ACE-I: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor-neprilysin inhibitor; AT: angiotensin; cGMP: cyclic guanosine monophosphate; DRI: direct renin inhibitor; MRA: mineralocorticoid receptor antagonist; RAAS: renin-angiotensin-aldosterone system.