Aldosterone: The hidden hormone linking hypertension and obesity, and a potential target
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Key takeaways:
- Dysregulated aldosterone production, sometimes driven by obesity, can cause hypertension.
- Targeted therapies that directly reduce aldosterone synthesis may help treat challenging cases of hypertension.
An op-ed published in February by Tom Frieden, MD, MPH, former director of the CDC, described hypertension as “the deadliest but most neglected and widespread pandemic of our time” — and he’s right.
As practicing cardiologists, we witness firsthand the toll on human health caused by high BP, from debilitating strokes and heart attacks to organ damage and premature death.
Hypertension is a leading modifiable risk factor globally for premature CV death, accounting for 10.8 million CV deaths and 11.3 million deaths globally in 2021. This and other alarming statistics underscore the immense public health challenge that persists:
- Nearly half of U.S. adults (48%) have hypertension, and 77% remain uncontrolled.
- The number of adults with uncontrolled hypertension is rising, surpassing 30 million.
- The estimated economic burden of hypertension in the U.S. is about $131 billion to $198 billion annually, making it a major health care cost driver.
There are several classes of antihypertensive drugs, more than 70 different generic medications and multiple combination therapies approved for the treatment of hypertension. While we’ve made great strides in managing this condition, these sobering numbers highlight the urgent need for more effective and targeted treatment strategies for the large number of patients whose BP remains uncontrolled.
Aldosterone’s role in hypertension
Various factors contribute to hypertension, but emerging research shines a spotlight on an underrecognized culprit: aldosterone.
Aldosterone, a steroid hormone produced by the zona glomerulosa layer of the adrenal cortex, plays an important role in maintaining sodium and water homeostasis. These classical effects are mediated through the mineralocorticoid receptor (MR).
However, a dysregulated or overactive aldosterone response can contribute to a cascade of harmful effects on the CV system, kidneys and metabolism. Emerging data have suggested the importance of MR-independent pathways in many of the deleterious effects, such as the G protein-coupled estrogen receptor 1 (GPER1) and its role in aldosterone-induced endothelial cell dysfunction.
The hidden hormone in hypertension
Not every case of hypertension involves dysregulated aldosterone, but studies suggest it plays a significant role in up to 30% of cases. Aldosterone exerts its influence through both MR-dependent and MR-independent pathways, ultimately leading to sodium and water retention and increased BP.
Patients with aldosterone-driven hypertension are at a higher risk for complications compared with those with classical hypertension, due to:
- increased risk for CAD, stroke and heart failure;
- metabolic syndrome and diabetes; and
- progression of chronic kidney disease.
The concern doesn’t stop there. The alarming rise in obesity rates during the past few decades presents a complex picture intertwined with hypertension. Obesity is a major risk factor for hypertension, contributing to 65% to 78% of cases, and research also reveals a strong link between obesity and dysregulated aldosterone levels.
Dysregulated aldosterone in individuals with obesity, for example, is both renin-dependent and renin-independent, but the individual driving mechanisms of the latter are complex. Researchers hypothesize that the adipocyte-derived hormone leptin represents a renin-independent pathway and is a direct regulator of aldosterone synthase expression, which in turn promotes elevated BP and CV dysfunction and other related conditions.
Treatment options old and new
Current standard of care medications like ACE inhibitors and angiotensin receptor blockers target the renin-angiotensin-aldosterone system (RAAS), but their focus is primarily on the renin-dependent pathway. Patients treated with ACE inhibitors/ARBs have an initial decline in aldosterone levels, as expected with RAAS inhibition, but up to 30% to 40% have an increase in aldosterone levels after longer-term treatment (termed aldosterone “breakthrough of escape”). Additional aldosterone inhibition may therefore be important for a sizable number of patients treated with ACE inhibitors/ARBs who continue to have suboptimal BP.
Mineralocorticoid receptor antagonists (MRAs) stand as the only available aldosterone-specific therapy, but their limitations are evident:
- anti-aldosterone effects only mediated by MR-dependent mechanisms, allowing continued aldosterone signaling through MR-independent mechanisms;
- increased plasma aldosterone concentration as a compensatory response, which may lead to even greater aldosterone signaling through MR-independent mechanisms;
- inferior outcomes compared with adrenalectomy for resistant hypertension;
- menstrual irregularities, sexual dysfunction and gynecomastia by binding to progesterone and androgen receptors; and
- potential adverse effects like hyperkalemia, hyponatremia and fatigue, restricting their use in specific patient groups.
Given the limitations of MRAs, additional targeted therapies that reduce aldosterone synthesis may be of benefit for patients with aldosterone-dependent hypertension, including investigational drugs like lorundrostat (Mineralys Therapeutics) and baxdrostat (AstraZeneca). These are the two latest-stage candidates in a new drug class, aldosterone synthase inhibitors (ASIs), and take a different approach by selectively targeting aldosterone via inhibiting the enzyme aldosterone synthase (CYP11B2). Selective inhibitors of aldosterone synthase have the potential to:
- offer a more targeted approach to hypertension management for patients with aldosterone-dependent (or contributing) hypertension;
- significantly decrease aldosterone levels without affecting cortisol and reduce all signaling pathways of aldosterone (both MR and non-MR effects); and
- improve rates of BP control, particularly for patients where aldosterone is a root cause of the condition.
One of these ASIs, lorundrostat, demonstrated an enhanced response for patients with a BMI of at least 30 kg/m2 (placebo-adjusted reductions in systolic BP of 16.7 mm Hg [P = .002] and 12.3 mm Hg [P = .03] with 50 mg and 100 mg once-daily doses, respectively), along with offering improved BP control across the general patient population in the Target-HTN trial published in September. These findings indicate that obesity may be an important endotype for identifying candidates for ASI therapy.
Additionally, a post hoc analysis from the trial showed that increased BMI was correlated with increased leptin circulation, which was consistent with emerging evidence of a leptin-driven, positive feedback loop between obesity, aldosterone and hypertension.
Where do we go from here?
As Frieden noted in his op-ed, getting 50% of all individuals with hypertension to their goal BP would prevent 2 million deaths each year and 200 million strokes and heart attacks during the next 25 years.
Further research is necessary, but ASIs represent a novel innovation and may offer a new treatment approach in the fight against hypertension, particularly for uncontrolled cases fueled by obesity-driven dysregulated aldosterone secretion without the unpleasant adverse hormonal effects of MRAs. Embracing and adopting well-tolerated treatment options in the future holds the potential to improve patient outcomes and incrementally alleviate the burden of hypertension.
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For more information:
Florian Rader, MD, MSc, is a board-certified cardiologist and hypertension specialist at Cedars-Sinai and medical director of its Hypertension Center of Excellence. He can be reached at florian.rader@cshs.org; X (Twitter): @raderflorian.
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