Issue: August 2020
Source/Disclosures
Source: Healio Interviews
Disclosures: Auchus reports he serves on advisory boards for or received consultant fees or grants from Adrenas Therapeutics, Corcept Therapeutics, Janssen, Millendo Therapeutics, Neurocrine Biosciences, Novartis, Quest Diagnostics, Selenity Therapeutics, Spruce Biosciences and Strongbridge Biopharma, and has served as a research investigator for Corcept Therapeutics, Millendo Therapeutics, Neurocrine Biosciences, Novartis, Spruce Biosciences and Strongbridge Biopharma. Findling reports he has served as a consultant and investigator for Corcept Therapeutics and Novartis. Vaidya reports he has received consultant fees from Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen and Selenity Therapeutics. Funder and Hammes report no relevant financial disclosures.
August 21, 2020
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Common and unrecognized, primary aldosteronism warrants more screening, targeted treatment

Issue: August 2020
Source/Disclosures
Source: Healio Interviews
Disclosures: Auchus reports he serves on advisory boards for or received consultant fees or grants from Adrenas Therapeutics, Corcept Therapeutics, Janssen, Millendo Therapeutics, Neurocrine Biosciences, Novartis, Quest Diagnostics, Selenity Therapeutics, Spruce Biosciences and Strongbridge Biopharma, and has served as a research investigator for Corcept Therapeutics, Millendo Therapeutics, Neurocrine Biosciences, Novartis, Spruce Biosciences and Strongbridge Biopharma. Findling reports he has served as a consultant and investigator for Corcept Therapeutics and Novartis. Vaidya reports he has received consultant fees from Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen and Selenity Therapeutics. Funder and Hammes report no relevant financial disclosures.
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Primary aldosteronism, an adrenal disorder and a secondary cause of hypertension, has historically been considered a rare condition.

Most hypertension is considered idiopathic by many clinicians; treatment is rarely aimed at an underlying mechanism, such as primary aldosteronism.

New research may change that thinking. In a cross-sectional study of more than 1,000 adults published in May in Annals of Internal Medicine, researchers measured the degree of renin-independent aldosterone production in every BP category — including normal levels — and estimated the prevalence of biochemically overt primary aldosteronism at 11.3% among normotensive adults and higher at 22% among those with resistant hypertension.

“Our study showed the whole distribution of renin-independent aldosterone production, and the distribution suggests that there is too much aldosterone being made on a broad severity spectrum from mild to very severe,” Anand Vaidya, MD, MMSc, director of the Center for Adrenal Disorders at Brigham and Women’s Hospital, associate professor of medicine at Harvard Medical School and a co-author of the study, told Endocrine Today. “This redefines primary aldosteronism not as a categorical or binary diagnosis, but as a syndrome that exists on a severity spectrum. This may seem counter-intuitive for many clinicians, because it has been ingrained since medical school that this is some rare entity that exists as a yes-or-no phenomenon.”

With an estimated 103 million adults living with hypertension in the United States, according to the American Heart Association, the findings are leading to calls for stepped up screenings and more targeted treatments, which are shown to substantially reduce morbidity and mortality.

Contrary to current teaching, primary aldosteronism is not a categorical diagnosis, but a syndrome with a spectrum of severity, according to Anand Vaidya, MD, MMSc.

Photo by Nancy Lange-Vaidya. Printed with permission..

“There is no question at this point that primary aldosteronism is an extraordinarily common disorder among people with hypertension,” James Findling, MD, director of community endocrinology services and clinical professor of medicine at the Medical College of Wisconsin in Milwaukee, told Endocrine Today. “Whether the percentage is 5%, 10%, 15%, I don’t think it really matters. Even 5% of a big number is a big number. This amplifies the point that all patients with hypertension should be considered for screening.”

The need for treatment is urgent. Studies show patients with primary aldosteronism have markedly increased risks for cardiovascular and cerebrovascular events, including stroke and coronary artery disease, compared with those with essential hypertension with a similar BP level.

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“We need to face the fact that half a million people, at least, worldwide, are in a state of double jeopardy,” John W. Funder, MD, PhD, FRACP, FRCP, senior fellow at the Hudson Institute of Medical Research and a professor in the department of medicine at Monash University in Australia, told Endocrine Today. “The double jeopardy is the CV damage due to hypertension coupled with the threefold increased risk profile of primary aldosteronism over and above ‘normal’ essential hypertension. That translates to premature mortality and increased morbidity. The costs of that are extraordinary.”

The ‘tip of the iceberg’

Hyperaldosteronism, characterized by nonsuppressible, renin-independent aldosterone production, produces inappropriate sodium retention and potassium loss, leading to BP elevation and an increased risk for adverse CV outcomes. Targeted treatments are available to mitigate CVD in individuals with primary aldosteronism, but the condition is “grossly underdiagnosed, even among high-risk patients with hypertension who clearly meet indications for diagnostic testing,” Vaidya and colleagues wrote.

Current guidelines recommend screening for primary aldosteronism in patients who have severe hypertension or hypertension along with hypokalemia, sleep apnea or an adrenal mass. An elevated aldosterone-renin ratio (ARR) and aldosterone level are considered positive screening for primary aldosteronism. Diagnosis can be confirmed with dynamic testing, such as oral sodium or IV saline loading, fludrocortisone suppression or captopril challenge.

Primary aldosteronism is often detected in patients with hypertension who are screened, but the researchers cited growing evidence that renin-independent aldosterone production is more prevalent than currently believed, even among patients who do not have a high ARR, hypertension or hypokalemia.

“Because we need some practical definition for primary aldosteronism, we put in place some arbitrary thresholds,” Vaidya said. “Those arbitrary thresholds, it turns out, are pretty strict, and they are only catching the tip of the iceberg.”

James Findling

For the Annals of Internal Medicine study, Vaidya and colleagues evaluated the presence of nonsuppressible renin-independent aldosterone production and biochemically overt primary aldosteronism — defined by international guidelines as an aldosterone excretion rate of at least 12 g per 24 hours in the context of high sodium balance and suppressed renin activity — in relation to BP among 1,015 patients at four academic medical centers in the United States.

The cohort included participants with normal BP (n = 289), stage 1 hypertension (n = 115), stage 2 hypertension (n = 203) and resistant hypertension (n = 408). All participants were assigned a high-sodium diet and standardized potassium intake for 5 to 7 days. Participants then completed a 24-hour urine collection and were assessed for BP and circulating levels of renin, aldosterone and electrolytes. Biochemically overt primary aldosteronism diagnoses were confirmed using this oral sodium suppression test.

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“[The researchers] did this in a very take-no-prisoners way,” Funder said. “Giving the participants 200 mEq to 300 mEq of sodium a day would normally be a crippling diet for a person with hypertension. I think they did that to be absolutely sure. For example, when the authors set the urinary excretion of aldosterone at 10 g per day rather than 12 g per day, the levels of primary aldosteronism were much higher — for example, 60% in resistant hypertension.”

John W. Funder

The mean adjusted levels of urinary aldosterone were 6.5 g per 24 hours (95% CI, 5.2-7.7) among patients with normal BP; 7.3 g per 24 hours (95% CI, 5.6-8.9) among patients with stage 1 hypertension; 9.5 g per 24 hours (95% CI, 8.2-10.8) among patients with stage 2 hypertension; and 14.6 g per 24 hours (95% CI, 12.9-16.2) among patients with resistant hypertension. For comparison, the current definition of overt primary aldosteronism is arbitrarily set at a urinary aldosterone level of 12.0 g per 24 hours.

The adjusted prevalence of biochemically overt primary aldosteronism corresponded with urinary aldosterone levels, and primary aldosteronism was “much higher” than normally seen in every BP category, Vaidya and colleagues wrote.

“This confirmed what a lot of us have been trying to say for a long time, that it only takes a little bit of aldosterone to cause hypertension when you have a high-salt diet,” Richard Auchus, MD, PhD, professor of pharmacology and internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan, told Endocrine Today. “That is the take-home message. We have known this, but we haven’t had a study that demonstrated it in as many people as this one.”

CV consequences

Primary aldosteronism markedly increases risks for CV and cerebrovascular events, including stroke and CAD, compared with essential hypertension, and that risk persists even with mineralocorticoid antagonist therapy, according to two analyses published in The Lancet Diabetes & Endocrinology in 2018. In the studies, the association was independent of BP, age and sex, suggesting that aldosterone can induce CV effects through mechanisms that are at least partly independent of its effects on BP, according to the researchers.

“There have been several studies that show you can reduce CV outcomes for patients who have hyperaldosteronism, if you can treat them,” Stephen R. Hammes, MD, PhD, the Louis S. Wolk Distinguished Professor of Medicine, chief of the division of endocrinology and metabolism and vice chair for research and academic affairs at the University of Rochester School of Medicine and Dentistry, told Endocrine Today. “In people with hyperaldosteronism, the CV outcomes are worse compared with patients who have similar degrees of hypertension, but do not have hyperaldosteronism. The thought is that having high aldosteronism does something outside of blood pressure, so that controlling it can be helpful.”

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In a systematic review and meta-analysis, Silvia Monticone, MD, of the division of internal medicine and hypertension unit at the University of Turin, Italy, and colleagues analyzed data from 31 studies conducted through February comparing adults with primary aldosteronism (n = 3,838; mean age, 53 years; 28% women) and adults with essential hypertension (n = 9,284; mean age, 53 years; 32% women). Researchers assessed the association between primary aldosteronism and incidence of stroke and CAD, which were coprimary endpoints, and secondary endpoints that included the prevalence of atrial fibrillation, heart failure, metabolic syndrome and diabetes. The cohorts were followed for a mean of 8.8 years.

Compared with adults diagnosed with essential hypertension, six studies found that those with primary aldosteronism had a higher incidence of stroke (OR = 2.58; 95% CI, 1.93-3.45) consistently across both matched and unmatched studies. In eight studies assessing risk for CAD, adults with primary aldosteronism also had a higher risk vs. those with essential hypertension (OR = 1.77; 95% CI, 1.1-2.83). Adults with primary aldosteronism also saw increased risks for atrial fibrillation (OR = 3.52; 95% CI, 2.06-5.99) and heart failure (OR = 2.05; 95% CI, 1.11-3.78) compared with those who had essential hypertension. There were no between-group differences for patients with aldosterone-producing adenomas or bilateral adrenal hyperplasia, according to researchers.

Patients with primary aldosteronism also had increased risks for diabetes, metabolic syndrome and left ventricular hypertrophy compared with those who had essential hypertension.

“If this is a common problem, it raises the stakes even more,” Vaidya said. “Are we missing an opportunity to modify individuals’ risk by targeting aldosterone? Our study does not address that, but it opens the scope on the magnitude of this problem.”

Lack of screening

Many adults with hypertension do not undergo screening for primary aldosteronism, and those who do often receive suboptimal care, making the condition a “major public health issue” that must be addressed by physicians, Funder and colleagues wrote in an updated clinical practice guideline released by the Endocrine Society in 2016.

In the guideline, researchers said more patients with primary aldosteronism will benefit from demand-driven diagnosis and effective treatment, including targeted mineralocorticoid receptor antagonist therapy.

“The current Endocrine Society guidelines recommend that people with severe or resistant hypertension and/or hyperkalemia be screened for primary aldosteronism, yet less than 3% of those severe cases are ever screened,” Findling said. “The idea that we should be expanding it to everybody ... it is a little hard to have that conversation when even among the most obvious cases, only 3% are being screened.”

Auchus said many primary care physicians and other clinicians do not appreciate how common hyperaldosteronism is.

Richard Auchus

“Of those screened, maybe 5% to 10% should go onto an endocrinologist — and we may not do further testing — but it is important to label the hypertension as aldosterone-mediated hypertension,” Auchus said. “We used to think of 90% of hypertension being essential or primary. In fact, it is the other way around: 80% of hypertension is secondary hypertension, and only a few percent have it for other reasons, like sleep apnea. By and large, the cause is salt and aldosterone. We need to re-paint the picture of hypertension.”

Data from Germany and the United Kingdom show that only 1 in 1,000 patients with hypertension are screened for primary aldosteronism, Funder wrote in an editorial accompanying the Annals of Internal Medicine study, adding that PCPs “just try to control BP.”

“As endocrinologists, we need to take some of this blame that we have not done a good enough job teaching in medical school and getting the word out to primary care and internal medicine about primary aldosteronism, that this is a common problem that needs to be screened for with anyone in whom hypertensive therapy is being considered,” Findling said. “It is clearly one of the most — if not the most — underdiagnosed clinical condition of importance, in my judgment, in clinical endocrinology.”

Increasing detection, treatment

For Vaidya, ideal management of primary aldosteronism would be to perform a comprehensive workup for any person suspected of having the condition, which could proceed as far as adrenal vein sampling.

“We do not live in that world,” Vaidya said. “I work at a tertiary care practice and I am a specialist, so I see referrals. I also find the evaluation and workup to be challenging. It takes time and energy. If you don’t have resources, it can be difficult. Our patients also find it challenging.”

Stephen R. Hammes

Still, there are simple steps that can lead to more people receiving the treatment they need, he said. In the primary care setting, any patient with suspected primary aldosteronism should have renin and aldosterone measured. If renin level is suppressed, that alone should be enough to act in a low-resource setting.

“If you know a patient has bad hypertension and a low renin, and you are unable to fully evaluate for primary aldosteronism, rather than doing nothing, you could prescribe a mineralocorticoid receptor antagonist,” Vaidya said. “Whether you know if they have primary aldosteronism or not, that is a great drug to give. It has a high probability of working, it is generic and safe, and it has been around for decades.”

Hammes said clinicians who screen patients should always consider the renin level, independent of the aldosterone level, and consider an appropriate dose of mineralocorticoid receptor antagonist.

“When renin levels are low, regardless of the aldosterone level, that is a sign that one should conduct a more significant screening test,” Hammes said. “Some of these studies using medical management show that if you can get the renin back into the normal range by giving them enough of a [mineralocorticoid receptor antagonist], those are the people who fare the best. Even with [mineralocorticoid receptor antagonists], studies show people are undertreated.”

Prescribing a mineralocorticoid receptor antagonist for any patient with hypertension and low renin can ensure people with primary aldosteronism do not “slip through the cracks,” Vaidya said.

“You either have the resources to go all the way or you can stop at any point before that and treat with a mineralocorticoid receptor antagonist, because it is effective and safe,” Vaidya said. “This is not all evidence based. There are no randomized controlled trials to support all of these decision trees. But decisions still have to be made, whether you work in rural Italy, or Japan, or Iowa or Boston. They need to be flexible, so that everyone has the ability to do their best to increase detection or empiric treatment.”