Resistant Hypertension Explained By Underlying Endocrine Imbalance

Researchers uncovered excess aldosterone as cause of antihypertensive treatment failure, and shed light on mechanisms to support breakthrough treatment success in resistant hypertension.

With Morris Brown, MD, PhD, and  David A. Calhoun, MD

Upwards of half of all patients with hypertension, have a resistant form the disease, meaning a blood pressure of 140/90 mmHg or greater despite treatment with a diuretic and two other medications.1-3 This subset of hypertensive patients presents an ongoing and important treatment challenge given their even greater risk of cardiovascular morbidity and mortality.

The British research group, who conducted the PATHWAYS-2 study, demonstrated that low-dose spironolactone (Aldactone) or amiloride (Midamor) when added to other standard blood pressure drugs worked better than comparator medications.4  Substantiating these findings, they have gone further to identify the mechanism behind this intractable form of hypertension—an aldosterone hormone imbalance--that offers a clearer understanding of the  functionality behind the efficacy of spironolactone in reducing blood pressure levels.5 Uncovering the mechanism buttressed support for their initial findings.4,5

Hormone imbalance explains resistant to blood pressure lowering treatment.

"Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion," said senior investigator Morris Brown, MD, PhD, professor of endocrine hypertension at Queen Mary University of London, and his colleagues.

He told EndocrineWeb: "We were thinking that a large portion of this [resistant hypertension] group has previous, undetected primary aldosteronism." After one patient in the initial study had an aldosterone-producing nodule removed from his adrenal gland, his blood pressure dropped to normal levels without drugs, Dr. Brown said, which led the team to explore this relationship further.

Findings Suggest New Regimen for Resistance Hypertension

The magnitude of the systolic blood pressure decline achieved with spironolactone in those with the lowest plasma renin concentrations—20 mm on average—can be considered ''extraordinary”, according to by David A. Calhoun, MD, FAHA, professor of medicine and medical director of the Vascular Biology and Hypertension Program at the University of Alabama at Birmingham, in an accompanying editorial.6

In the 2015 study, the researchers' observed an inverse relationship between the renin concentration and the antihypertensive results of spironolactone ''provided indirect evidence that blocking the mineralocorticoid receptor treats resistant hypertension by overcoming or at least diminishing excess fluid retention," Dr. Calhoun said.

''These findings clearly demonstrate that resistant hypertension is related to persistent fluid retention,'' he told EndocrineWeb, ''and they further showed that a large and important cause of that fluid retention is aldosterone excess. So effective treatment is going to require effective diuretic therapy.''

Review of PATHWAY-2 Research and Rationale for Pursuing Substudies

This year-long, double-blind, placebo-controlled, randomized, crossover PATHWAY-2 trial was conducted at 12 secondary care sites and two primary care sites, all in the United Kingdom.4 Patients ranged in age from 18 to 79 years old and had a systolic blood pressure of at least 140 mmHg despite treatment with maximum tolerated doses of three blood pressure-lowering drugs (ACE or ARB, thiazide-type diuretic, and calcium channel blocker). Daily low dose spironolactone (25 to 50 mg) added to standard blood pressure-lowering treatment was more effective than either placebo, or two alternative drugs studied —isoprolol and doxazosin.4

As strong as the findings were, in order for the results of PATHWAY-2 to change practice, the researchers said, ''it was important to show a mechanistic basis underpinning the superiority of spironolactone."5

PATHWAY-2 Mechanisms: A Closer Look

The researchers pursued an examination of whether amiloride could be an alternative if spironolactone was not tolerated due to side effects such as gynecomastia or erectile dysfunction.5

The new findings are based on three substudies:

  • substudy 1—plasma aldosterone, renin and aldosterone-to-renin ratio (n=126)
  • substudy 2—hemodynamic analyses (n=226)
  • substudy 3—the amiloride open label run-out study (n=146). 

Baseline characteristics among the three participant groups were similar: average 60 years of age, 70% men, 10 to 17% had diabetes, and body weight of 94 kg (207 lbs).5

Mean baseline clinic blood pressure in the overall trial population was 157.4/90.3 mmHg (SD 14.3-11.5). Baseline electrolytes and estimated glomerular filtration rate were normal; 24-hour urinary sodium concentrations were about 150 mmol (equivalent to a 9 g of daily salt intake).5

Superiority of Spironolactone in Reversing Resistant Hypertension  

Blood pressure lowering response to spironolactone in substudy 1 was predicted by baseline ARR  (r2=0.13, p<0.0001), followed by plasma renin, and was greatest in those whose plasma renin was suppressed and weakly predicted by aldosterone alone.5 No links were found between baseline plasma renin, aldosterone or the ARR and the blood pressure response in those taking placebo, doxazosin or bisoprolol.

The findings from these substudies also demonstrated that spironolactone was superior to other antihypertensive drugs in reducing indices of salt and water retention, that is, this medication promoted the reduction in blood pressure primarily by enhancing diuretic activity.5

Blood pressure in patients after six weeks on amiloride was similar to the patients' previous measurements on spironolactone and was much lower than those receiving either placebo or the other of two active treatments (P < 0.0001). While that study was not randomized, Dr. Brown indicated that the similar results were reassuring.

"Both [spironolactone and amiloride] reduced blood pressure by 18 and 20 mmHg," Dr. Brown said; spironolactone was dosed at 25 mg and the dose of amiloride was 10 mg daily.4,5

Clinical Practice Implications for Patients with Resistant Hypertension

Dr. Brown cited the patient who had a 6 mm nodule surgically removed from an adrenal gland who was previously taking four antihypertensive medications with uncontrolled blood pressure (BP) of 160/100 mmHg, yet post-op, ''his BP was 130/90 mmHg with no drugs. The nodule in the adrenal [if one is found] is churning out the aldosterone and causing the hypertension."

While the study was conducted in the UK, the findings would no doubt apply to the US population as well, Dr. Brown said. "There's no reason to suggest otherwise," he told EndocrineWeb. "and, there have been smaller studies [with similar findings]."  

Given the lack of awareness about how common this condition is, he suggests, “if a patient presents with resistant hypertension, you should be very suspicious of a diagnosis of primary aldosteronism."

The study was funded by a special project grant from the British Heart Foundation, with further funding provided by the UK National Institute for Health Research (NIHR) Comprehensive Local Research Networks.

Dr. Calhoun has no relevant disclosures. Dr. Brown reports consulting fees from GSK, Mitsubishi-Europe, and Heptares, and the other study authors reported further financial disclosures. 

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