Current Treatment Challenges

CURRENT TREATMENT Challenges

Are you cycling through antihypertensive medications? Consider an underlying, underrecognised mechanism  of HTN that’s hard to control^[1a]

The RAAS limitation in hard-to-control HTN:
Aldosterone production inhibition is not directly
addressed by current antihypertensives^{[3a],[4a],[5a],[6a]}

	ACEis and ARBs	CCBs	BBs	MRAs
Directly address aldosterone production^{[3b],[4b],[5b],[6b]}
Effect on aldosterone levels^{[7],[8],[9],[10],[11]}	~3%–16%, followed by escape with ACEis^[*]	~0%-17%^[†]	~62%^[‡]	~25%–120^[%],[§]
How current treatments work^{[3c],[4c],[12a],[13a],[14a],[15a],[16a],[17a]}	ACE inhibitors reduce angiotensin II formation, and ARBs block the angiotensin II type 1 receptor; both actions reduce vasoconstriction^[12b],[13b]	Prevent calcium from entering the cells of blood vessels which causes them to relax and widen^[14b]	Lower renin release by blocking specific receptors in the kidneys^[15b],[16b]	Block aldosterone at the mineralocorticoid receptor, reducing sodium retention and fluid buildup—may also cause compensatory increases in circulating aldosterone^{[3d],[4d],[17b]}

ACEis and ARBs

Directly address aldosterone production^{[3b],[4b],[5b],[6b]}

Effect on aldosterone levels^{[7],[8],[9],[10],[11]}

~3%–16%, followed by escape with ACEis^[*]

How current treatments work^{[3c],[4c],[12a],[13a],[14a],[15a],[16a],[17a]} ACE inhibitors reduce
angiotensin II formation, and
ARBs block the angiotensin II
type 1 receptor; both actions
reduce vasoconstriction^[12b],[13b]

CCBs

Directly address aldosterone production^{[3b],[4b],[5b],[6b]}

Effect on aldosterone levels^{[7],[8],[9],[10],[11]}

~0%-17%^[†]

How current treatments work^{[3c],[4c],[12a],[13a],[14a],[15a],[16a],[17a]} Prevent calcium from entering
the cells of blood vessels
which causes them to relax
and widen^[14b]

BBs

Directly address aldosterone production^{[3b],[4b],[5b],[6b]}

Effect on aldosterone levels^{[7],[8],[9],[10],[11]}

~62%^[‡]

How current treatments work^{[3c],[4c],[12a],[13a],[14a],[15a],[16a],[17a]} Lower renin release by
blocking specific receptors
in the kidneys^[15b],[16b]

MRAs

Directly address aldosterone production^{[3b],[4b],[5b],[6b]}

Effect on aldosterone levels^{[7],[8],[9],[10],[11]}

~25%–120^[%],[§]

How current treatments work^{[3c],[4c],[12a],[13a],[14a],[15a],[16a],[17a]} Block aldosterone at the
mineralocorticoid receptor,
reducing sodium retention
and fluid buildup—may
also cause compensatory
increases in circulating
aldosterone^{[3d],[4d],[17b]}

ACEis=angiotensin-converting enzyme inhibitors; AF=atrial fibrillation; AHA=American Heart Association; ARBs=angiotensin receptor blockers; ARR=absolute risk reduction; AUC=area under the curve; BB=beta blocker; BP=blood pressure; CCB=calcium channel blocker; ESC=European Society of Cardiology; HTN=hypertension; MRAs=mineralocorticoid receptor antagonists; PA=primary aldosteronism; PAC=plasma aldosterone concentration; RAAS=renin-angiotensin-aldosterone system.

*^{^}

Based on a randomized, open-label trial that assessed aldosterone escape in patients with mild to moderate HTN (n=63) treated for 12 weeks with antihypertensives, including an ACEi, an ARB, a diuretic, or an ACEi+ARB combination. From Week 0 to Week 12, quinapril (20 mg/day) lowered plasma aldosterone by 15.8% (7.6 to 6.4) and irbesartan (150 mg/day) lowered aldosterone by 2.5% (8.0 to 7.8), while aldosterone levels increased by 55% with a hydrochlorothiazide diuretic (25 mg/day; 9.1 to 14.1) and by 87% with irbesartan+quinapril (150 mg/day + 20 mg/day; 6.9 to 12.9).

^{† ^}

In a randomized study in patients with HTN and suspected PA (n=230) that evaluated the effects of single antihypertensive therapies (atenolol, amlodipine, doxazosin, fosinopril, and irbesartan) on ARR, amlodipine (10 mg/day) reduced ARR by 16.98% (±32) after 2 months of treatment (p<0.001). In a separate study that evaluated serum aldosterone levels in 144 hypertensive patients, 19 patients with PA, and 37 normotensive patients (patients were on different treatment regimens, such as single drug or combination therapy with BBs, ACEis or ARBs, CCBs, and no treatment), CCB therapy had no influence on serum levels of aldosterone.

^{‡ ^}

In a randomized study of patients with HTN with suspected PA (n=230) that evaluated the effects of single antihypertensive therapies (atenolol, amlodipine, doxazosin, fosinopril, and irbesartan) on ARR, atenolol (100 mg/day) increased ARR by 62% (±82) after 2 months of treatment (p<0.0001).

^{§ ^}

In one study that evaluated the effects of spironolactone (25 mg/day) on PAC in patients with resistant HTN (n=39), PAC increased from 15.4 to 19.2 after 6 months of therapy. In a separate study of healthy volunteers who received eplerenone (100 mg/day) for 10 days (n=10), a 120% increase in aldosterone AUC was observed.

References:

^{1a 1b} Brown JM et al. Ann Intern Med. 2020;173(1):10–20.

^{^} Jones DW et al. J Am Coll Cardiol. 2025;86(18):1567–1678.

^{3a 3b 3c 3d} Scott JH et al. Physiology, aldosterone. StatPearls [internet]. Updated 1 May 2023. Accessed 11 November 2025. https://www.ncbi.nlm.nih.gov/books/NBK470339/

^{4a 4b 4c 4d} Hargovan M et al. JRSM Cardiovasc Dis. 2014;3:1–9.

^{5a 5b} Sato A et al. Hypertens Res. 2006;(4):211–216.

^{6a 6b} Jędrusik P et al. Front Pharmacol. 2021;12:684111.

^{^} Ubaid-Girioli S et al. J Clin Hypertens (Greenwich). 2007;9(10):770–774.

^{^} Mulatero P et al. Hypertension. 2002;40(6):897–902.

^{^} Seifarth C et al. Clin Endocrinol (Oxf). 2002;57:457–465.

10.

^{^} Ubaid-Girioli S et al. J Clin Hypertens (Greenwich). 2009;11(5):245-252.

11.

^{^} Eudy RJ et al. J Transl Med. 2011;9:180.

12.

^{12a 12b} Jugdutt BI. Circulation. 2015;131:1380–1383.

13.

^{13a 13b} von Lueder TG et al. Cardiovasc Drugs Ther. 2013;27:171–179.

14.

^{14a 14b} Elliot WJ et al. J Clin Hypertens (Greenwich). 2011;13:687–689.

15.

^{15a 15b} Struyker-Boudier HA et al. Am J Hypertens. 1989;2(11Pt2):237S–240S.

16.

^{16a 16b} Blumenfeld JD et al. Am J Hypertens. 1999;12:451–459.

17.

^{^} Jadhav U et al. Cureus. 2023;15(9):e45241.

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