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68 Ga-pentixafor is a radionuclide imaging ligand specifically targeting CXCR4 ( 173 ). In 63 patients with PA who were treated surgically, 68 Ga-pentixafor PET-CT was noninferior to AVS in diagnosing lateralizing PA ( 174 ). | 63 | 27 | 27 | b0802b80969b3debc3963d884c5266a8b69fcd2cfe81cace9060b8f33e5a0467 |
Suppressed vs Unsuppressed Renin in Individuals With Primary Aldosteronism Receiving Primary Aldosteronism–Specific Medical Therapy Background Although aldosterone-directed medical therapy has been shown to be beneficial in primary aldosteronism (PA), the op - timal approach to dosing and surveillance is uncertain. | 66 | 27 | 27 | 9e33c5ea745ad7fd93e0743b199d7cc0bd735bc8fa4a7cdf70fac0ef7b8d0432 |
Whether renin should be used to guide treatment has been considered in prior studies and by consensus groups. The premise of using renin as a biomarker of PA-specific medical therapy stems from the general knowledge of the physiology of endocrine hormone excess (ie, decline in hormone excess or activity is reflected in... | 73 | 27 | 27 | d3ee2862a091b47bfa11b1ea2d62306ea8a6d8f644832d27c44ce6396c92d33f |
Since PA is characterized and diagnosed by aldoster - one production despite suppression of renin and angiotensin II, a rise in renin induced by aldosterone-directed medical therapy should reflect the reversal of PA pathophysiology that may portend improved clinical outcomes ( 175 ). | 58 | 27 | 27 | 331ad25492d3b0e523b6cc6533e0c6e630b38d4e1e1d592eb9ba98a2d70a70b5 |
Question 7. Should suppressed renin vs unsuppressed renin be used in individuals with primary aldosteronism receiving primary aldosteronism–specific medical therapy? The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. | 56 | 27 | 27 | b3ca32f9ad3872916567a2a7d279c62989edbe1a5509d66f297bd2f7bd29bacd |
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Recommendation 7 In individuals with primary aldosteronism (PA) receiv - ing PA-specific medical therapy whose hypertension is not controlled and renin is suppressed, we suggest increasing PA-specific medical therapy to raise renin (2 | ⊕ OOO). | 56 | 28 | 28 | a000cb20019f307e3c2c3781295271f2a7cf7f7b92a47716b8aec956702a403b |
Technical remarks: • This recommendation applies to individuals with PA receiving aldosterone-directed medical ther - apy whose blood pressure (BP) remains high. Uncertainty remains as to whether titrating aldosterone-directed medical therapy to raise re - nin when BP is controlled is efficacious. | 60 | 28 | 28 | 6ed41a07937da2376e9e8e6df2d91a4de69f155f7fe330e422afdc75d2784e89 |
• The panel does not specify a renin level to target but rather advises titration of aldosterone-directed medical therapy to a rise in renin from pretreat - ment baseline. Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at h... | 94 | 28 | 28 | 0a5e354fc3d4cb6298ac90f5c33918ccbc8f90cd0c00833c6e1e3b6ba5e23a6b |
Benefits and Harms The panel voted for the following patient-important outcomes for Question 7 decision making: 1) percent of individuals achiev - ing BP control, 2) number of antihypertensive agents, 3) dosage of antihypertensive agents, 4) systolic BP (SBP) level, 5) major ad - verse cardiovascular events (MACEs), 6)... | 126 | 28 | 28 | 296b7c9fd52b46f9f1a560600f3ec687ad5bdd09b5b3a59c4211814f7aea303b |
Our systematic review ( 53 ) identified 11 studies that evaluated the impact of increasing renin with aldosterone-directed medical therapy when compared with persistently suppressed renin. When compared with unsuppressed renin, suppressed renin dur - ing aldosterone-directed medical therapy was associated with in - cre... | 91 | 28 | 28 | 31123174a3a72a4817663750d6b30ee3eb9838e3236a270dd88fee6bd6622e8a |
There were no statistically significant differences in MACEs (eg, ischemic heart disease, heart failure) in the meta-analysis. In indi - vidual retrospective cohort studies, a rise in renin to a level higher than 1.0 ng/mL/h was associated with lower risk for MACEs when compared with persistently suppressed renin ( 7 ,... | 79 | 28 | 28 | 7536e5b954b36c373a36724c95a5aeb2b4313131001fa1ffb2d56dc7fa97dca0 |
In this regard, the addition of renin measurements does not pose a substantial increase in resource utilization. However, the add - itional costs of measuring renin may be a limiting factor or pro - hibitive to some clinicians and increase health disparities. | 51 | 28 | 28 | 2618825437f5f191d97eb23e4bbbd3ac312805faee4df298d5419381c21e0abf |
In balance, targeting a rise in renin may be associated with a lower risk of death, stroke, and atrial fibrillation, but the pooled analysis did not demonstrate statistically significant re - duction in the risk for MACEs. | 49 | 28 | 28 | 29c59d8d0e89726fb57d29bf065089bbab97133d571687deb3964ce8a67be0dd |
Evidence to Decision Factors • No studies were found that assessed the cost-effectiveness of targeting renin in PA-directed medical therapy. • There is an obligate cost associated with measuring renin and measuring it frequently during longitudinal care. | 47 | 28 | 28 | 8e7819fe5ace5456800c513f91e50ca90c858a9231a5df501c49cf367bcf1de7 |
• If the studies suggesting that increasing renin with min - eralocorticoid receptor antagonist (MRA) therapy can mitigate some of the risk for incident cardiovascular and kidney disease are confirmed or validated, the additional cost of measuring renin is likely to be cost-effective. | 57 | 28 | 28 | 233584b16ff9c5dcd8d92e945f81ae23a762469893f8de7cc6951d51fe54e064 |
• No studies were found that assess the impact of targeting renin in PA-directed therapy on health equity. • As stated, the costs of measuring renin, in addition to the standard longitudinal follow-up and monitoring for med - ical therapy for PA, may be a limiting factor for some clini - cians (specifically in areas wh... | 78 | 28 | 28 | ab04c68e8b81763118f83d458e8dd565f457587dc98aac81dbf588a9856347ef |
• No research evidence was identified for acceptability by the health care workers or feasibility. • Measurement of renin to guide medical therapy is likely feas - ible at most centers that routinely treat individuals with PA. | 43 | 28 | 28 | f2bae773447153078e7d99b89517f06b8c4d50d9c5212c8f23cb14e4b5753cb6 |
Justification for the Recommendation Because the pathophysiology of PA in most individuals man - ifests with suppressed renin, a rise in renin with MRA therapy serves as a biomarker indicating a restoration of physiology (ie, sufficient mineralocorticoid receptor [MR] blockade and reduction in extracellular volume) ( 1... | 69 | 28 | 28 | 02ecfa9be8eafc502d69ef21fdc71e43a2702935e945191fdb6e081ba27e4045 |
The summary of sev - eral observational studies suggests that this practice is associ - ated with statistically lower risks of death and atrial fibrillation as well as a lower number of antihypertensive med - ications and risk for hypokalemia. | 54 | 28 | 28 | 5d6098c88c55ea9efb4f0116e6a63eaa9ecfff4a64f101f5c938d1e829ff8e96 |
Importantly, the primary clinical objective of MRA therapy remains normalizing BP with the fewest number of medications (and normalizing po - tassium, when applicable); however, achieving a rise in renin is suggested as an additional objective that reflects a better prognosis ( 175 ). | 57 | 28 | 28 | 498c0a4e698035c12386c3b26341235cde140e9c4e0a26546d74a3e730e58d39 |
Caveats to this approach include that this evidence stems from observational studies susceptible to bias and residual confounding, that there is no direct evidence to dictate what renin threshold to target as optimal, that this approach may not be possible or feasible or necessary in all individuals, that there are dif... | 95 | 28 | 28 | 350f1cb4f6c6f1dc070bb406cade2b2ad4fc7cbe0c55c6ee10b654328fbd0f79 |
For these rea - sons, we suggest focusing on dose intensification of MRA therapy to raise renin, particularly in individuals whose BP is not controlled. Once BP is controlled, non-MRA medica - tions can be lowered or removed, when possible, thus allow - ing further increases of MRA dosing and attempts to raise renin ( ... | 75 | 28 | 28 | b1941c24fbb2308673bfff88ebff4b7144d395cb1af2c840d3be95115b623451 |
Furthermore, interpretation of renin levels may be hampered in individuals concomitantly receiving other medications that affect renin levels (eg, β -adrenergic blockers that lower renin or renin – angiotensin – aldosterone system [RAAS] inhibitors that may raise renin in synergy with MRAs). | 66 | 28 | 28 | e71c12f8ceb00a1343beee635c36422da8ccb687b878e90f22553991c6bc3fc7 |
Rather than targeting a specific renin thresh - old, we suggest that the observation that renin has in - creased from its pretreatment baseline should provide some reassurance of treatment efficacy. Consistent with this recommendation, a recent large international consen - sus group endorsed targeting a rise in renin w... | 115 | 28 | 28 | aa2a998c8a56f76655e9ab6ad6b8d67eddac512af9984bb6fbabbce8644c5e50 |
2480 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026 | 62 | 28 | 28 | 6e627c7ffc7dd4636f1c2f7c1aafc6d6bc4160d62b49b2cbce5cd470b6c3ebdf |
Comments Special populations: • Individuals with hyperkalemia/chronic kidney disease (CKD) stage 3 and above: Achieving an increase in renin with MRA therapy is challenging in individuals with CKD. | 46 | 29 | 29 | 5a8316aad4ed892e3d481eff43843034576fa7291c6b99ed4d0a723ec645eaed |
The ability to produce and secrete renin may be im - paired with advanced CKD and higher MRA doses, which may increase the risk for hyperkalemia. As such, targeting an increase in renin in CKD may not always be a feasible or practical clinical objective. | 58 | 29 | 29 | 3d447b34be3bf3fcdd12451f6c4507ac167b13b885163eb8a1f57056efa73919 |
However, since the nonsteroidal MRA finerenone has been shown to reduce adverse cardiovascular and kidney outcomes in 3 large randomized controlled trials (RCTs) of individ - uals with diabetes and CKD or heart failure ( 176-178 ), it is reasonable to treat individuals with PA and CKD with MRAs as long as serum potassi... | 74 | 29 | 29 | 580f798a65cd2e080175cb89280adaa51877f0cad9f55761a9ce1d8bdce9155a |
When encountering hyperkalemia in CKD, the use of concur - rent diuretics, sodium-glucose cotransporter (SGLT2) in - hibitors, and patiromer/novel potassium binders have all been shown to mitigate the risk of MRA-induced hyper - kalemia in RCTs ( 179 , 180 ). | 79 | 29 | 29 | 8ae7d34f1cdf38f0244f7d5e91c009aad7006634e9b1c782b7b29bad1a3c3c7c |
• Individuals taking medications that influence renin: The use of some concurrent medications may confound the in - terpretation of renin. β -Adrenergic blockers can lower re - nin secretion; therefore, individuals on high doses may not manifest an increase in renin with MRAs. | 59 | 29 | 29 | 81aad8d7c912a858030fd1a77d66b42270fb3284bd127025d886086cba33c0a5 |
High dietary so - dium intake can lower renin, whereas a sodium-restricted diet can increase renin ( 181 ); however, most of the global population consumes a relatively high dietary sodium con - tent known to expand intravascular volume and put downward pressure on renin. | 56 | 29 | 29 | 4c8d277ea3631d6c7c157d74a0ef9b0b03b1f578439c1ba61a50c7add6286254 |
The use of angiotensin- converting enzyme [ACE] inhibitors/angiotensin receptor blockers [ARBs] and diuretics can raise renin and thereby potentially confound the isolated effect attributable to MRA therapy. | 47 | 29 | 29 | 4e90d42225fc700f28f959e558d6a693cdada3f6dad8418207312ac750fbfa22 |
Research Considerations Current gaps in knowledge call for further research in the fol - lowing area: • Conducting prospective, randomized, controlled studies with surrogate outcomes (eg, cardiac imaging, vascular dynamics) and hard outcomes to robustly assess the effi - cacy of targeting a rise in renin with aldostero... | 123 | 29 | 29 | 8e3cc316ab2db0c30f5e441d644303906d7e5b258e9117b2ef9cd899196c6555 |
In individuals with primary aldosteronism (PA), 24-hour urine steroid metabolome studies and dexamethasone suppression tests in - dicate that autonomous cortisol secretion (ACS) is not uncom - mon. | 46 | 29 | 29 | d5c201c0cbede5dc1c0d6c3f260462580e0bef9a57ec253a2c2fef417d58a3b9 |
Furthermore, excess cortisol production in individuals with PA may affect interpretation of AVS results and/or lead to postoperative glucocorticoid deficiency in those with aden - omas co-secreting aldosterone and cortisol. | 48 | 29 | 29 | a4fc86ffac7bd9fd393e774291787ba700b823c889e780da5740eaaeaad5d4ec |
Question 8. Should a dexamethasone suppression test vs no dexamethasone suppression test be used in individuals with primary aldosteronism and adrenal adenoma? Recommendation 8 In individuals with primary aldosteronism (PA) and adrenal adenoma, we suggest a dexamethasone sup - pression test (2 | ⊕ OOO). | 83 | 29 | 29 | 885af86625175e69d709f58513b2b6e3980a1b4cde19de41c12a3fa846a4fc35 |
Technical remarks • A dexamethasone suppression test should be per - formed, and a positive test should prompt further evaluation for Cushing syndrome as detailed in the Endocrine Society Clinical Practice Guidelines. | 40 | 29 | 29 | 34cf79dc34bf58093b5bfeeaa13364883d90977d65d80a362205c0749c6125e1 |
• For the 1-mg overnight dexamethasone suppres - sion test, 1 mg dexamethasone is taken orally at 23:00 to 24:00 with serum cortisol measured at 08:00 to 09:00 the next morning. | 53 | 29 | 29 | 5fa30271643d972272d1d306048505e890ad4c8f47fde0c7ee1e038413f5392a |
A serum cortisol > 1.8 μ g/dL (50 nmol/L) suggests autonomous cor - tisol secretion (ACS). • For individuals with mild ACS, measuring plasma metanephrine during adrenal venous sampling (AVS) may help lateralize both aldosterone and cor - tisol secretion although further research is needed. | 72 | 29 | 29 | f90a9bd28e9b6c8c8114bb88f2268baaa0ec36ad02cf06daf28fffa73c0e8a19 |
It will also be important to measure early morning cortisol following adrenal surgery and prepare for a period of possible glucocorticoid insufficiency. Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines.... | 85 | 29 | 29 | 21c63e6ab87a83e5388b1437c01c970cbccffd95e6f17bba03f3ff3c0ddca581 |
Benefits and Harms The panel voted for the following patient-important outcomes for Question 8 decision making: 1) postoperative adrenal in - sufficiency, 2) ACS detection, 3) false lateralization, 4) AVS accuracy and 5) adverse events. | 54 | 29 | 29 | b59e3a88afae0297a375a05b5263175047a089a085f445ed46de7b25d0e40d81 |
As the systematic review did not identify any studies that directly address this question, additional relevant studies were evaluated. A number of retrospective cohort studies reported that ap - proximately 5% to 15% of individuals with PA have ACS as defined by a positive 1-mg dexamethasone suppression test with a cor... | 84 | 29 | 29 | 4ae0e825a79b95dd0d628f4118fe929f8b41033598aefd110bc49a532e2ebc90 |
A more recent systematic review of 16 studies published between 2000 and 2020, with data from 2862 indi - viduals with PA, reported a prevalence of 5% to 27% ( 187 ). | 41 | 29 | 29 | 78fbe8f258463bbac2cdf283c2339c6e7f9a7a573183cd34b59de4958bab50d2 |
Studies have also reported increased cardio-metabolic-renal complications in individuals with PA and concurrent cortisol excess. The adverse consequences include worse glucose tolerance and diabetes ( 188-191 ), higher left ven - tricular mass index ( 192 ), more cardiovascular events ( 189 , 193 ), osteopenia/osteopor... | 75 | 29 | 29 | e79ecdef3b4884faec99c7750e8f284073df1e3ad1bc13a7431cc6f8df6813d4 |
In individuals with PA who undergo AVS, studies indicate that ACS may complicate the interpretation of adrenal vein se - lectivity and lateralization of aldosterone production. Excess cortisol secretion may lead to lateralization of cortisol to The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. | 62 | 29 | 29 | 3daf036b5a859d72cb545495dea1541b20b20952e97f71e880ac88ede8796fc3 |
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one side with underestimation of aldosterone production, as reflected by the aldosterone to cortisol ratio, on the same side ( 182 , 196 , 197 ). Cortisol production on the contralateral side may be suppressed and lead to the false assessment of in - adequate adrenal vein cannulation ( 196 ). | 63 | 30 | 30 | 0c167b499b20669161cde0423fc8f65780b52d667e57e967f50f0864f144304e |
Current evidence suggests that measurement of plasma metanephrine, which displays minimum fluctuation during stress and a higher adrenal to peripheral gradient compared to cortisol ( 198 , 199 ), is useful in these cases to assess selectivity and lateralization. | 48 | 30 | 30 | c896b51a3ffaa21a1b990da6335d26ff353532053d24888fb16cc039cad87ff9 |
Suggested thresholds include selectivity index > 12 and lateral - ization index > 4 where metanephrine replaced cortisol in the assessment of selectivity and lateralization ( 197 , 199-203 ). | 40 | 30 | 30 | c8539a647eb253268a8cad38e09c2bc0c23d8eed0dd5d1d40757987b28732bb9 |
However, issues with selectivity of adrenal vein catheteriza - tion and lateralization of aldosterone production have not been reported in all studies ( 183 ), possibly because AVS inter - pretation was mainly affected in individuals with post- dexamethasone cortisol more than 5 ug/dL (138 nmol/L) ( 204 ). | 72 | 30 | 30 | 15f0f86d7fe26e6416b5b335d09cf88f1e7185635f31aae504f48f934622cef9 |
One study suggested that AVS performance under co - syntropin stimulation, instead of during unstimulated condi - tions, may overcome the need to measure metanephrines for the assessment of selectivity and lateralization ( 197 ). | 50 | 30 | 30 | eaae133feaaa4c68d3d100f08975f6c4da1b31166b747d41cf36af7c035e4632 |
For those with concurrent PA and ACS, surgical resection of the adrenal adenoma may lead to postoperative glucocorticoid insufficiency. A study of 108 individuals who underwent unilat - eral adrenalectomy for a range of reasons reported that 50% of those with concurrent PA and hypercortisolism (n = 12) devel - oped adr... | 104 | 30 | 30 | 3a4b0ebbe90a08cd1301f68f3d3be795cdc649d321aa58f3cec5e714d8c83292 |
The potential undesirable effect of performing a 1-mg dexa - methasone suppression test may be related to false-positive or false-negative results. False-positive results may lead to unneces - sary further investigations, although 24-hour urinary free corti - sol and midnight salivary cortisol are noninvasive and relat... | 72 | 30 | 30 | bcb86f4f9498d46911004efb5f313bbb833b3df687df1493e7b322f9cd11ab28 |
More invasive testing would only be conducted if multiple screening tests are positive. The dexamethasone sup - pression test is considered the most sensitive screening test, and false negatives are uncommon. A meta-analysis demonstrated a sensitivity of 98.6% (96.9%-99.4%), specificity of 90.6% (86.4%-93.6%), positive... | 111 | 30 | 30 | eddfdab3a0e42176152a3f7f7bf9f1cabda0e30cc1717346b98288d94eb5db02 |
False-positive results can occur due to failure to correctly take dexamethasone, interfering medications such as anticonvulsants and other CYP3A4 inducers that increase dexamethasone deg - radation, and malabsorption of dexamethasone ( 207 ). | 61 | 30 | 30 | a7cc58a42e4c3a9ff77a488f18db91f29909df44912545084a50ef0a00fbd09e |
This is - sue can be resolved with serum dexamethasone measurement. A range of other conditions may cause false-positive results, in - cluding oral estrogen use, obesity, major depression, alcohol use disorder, and acute illnesses. | 49 | 30 | 30 | bd5b2813af0d9ba98995065cd215f5319bc123316104fde6b9605bd0f61b7044 |
These are covered by guidelines for Cushing syndrome ( 208 ). Evidence to Decision Factors • The potential benefits obtained from doing a 1-mg dexa - methasone suppression test outweigh the potential harms, as outlined. | 43 | 30 | 30 | 2844ed3c18ce5e57a8fb19c7c64d0e3cd2cca7b079a607b7f599f7340e03b7a6 |
• The dexamethasone suppression test requires minimal re - sources, which include dexamethasone tablets and a blood test for plasma cortisol concentration, and it is widely available worldwide. • We did not find any published studies on the cost- effectiveness of conducting a 1-mg dexamethasone sup - pression test. | 69 | 30 | 30 | 5fed8ef0343fa41fe87348e15037eecd490b821b45dad7fd9487ffc4491dbd1d |
However, it is known to be a relatively cheap and commonly ordered test in endocrinology. • If the result is abnormal, 2 follow-up tests (24-hour urin - ary free cortisol and midnight salivary cortisol) are also accessible and inexpensive. | 55 | 30 | 30 | c3733e566b8119329ac94724259746788f212e9f328b8c882322d57a87f0f3a6 |
• Furthermore, an understanding of normal adrenal cortisol secretion will reduce confounding in the interpretation of AVS results. Repeating AVS due to uninterpretable results is much more expensive ( ∼ $2000-3000 USD) than doing a 1-mg dexamethasone suppression test ( ∼ $20) and plan - ning AVS accordingly. | 71 | 30 | 30 | 33317616521375ba36ea49a5c8f4dd59956ccf0a6f10428098bc1894df4c020d |
• Individuals rarely decline the dexamethasone suppression test in clinical practice. They may occasionally experience adverse effects from the dexamethasone, but these effects are transient, as the dose of dexamethasone is low and the medication is given only once. | 55 | 30 | 30 | 2f29d70df6dabe2aee12f1ad0669ac07ee39a08df087fbe35311913f6374ce46 |
Justification for the Recommendation The panel based its recommendation on evidence demonstrat - ing that ACS is not uncommon in individuals with PA and can be detected by dexamethasone suppression testing. Having ACS may lead to adverse cardiometabolic consequences, com - plicate the interpretation of AVS results, and... | 81 | 30 | 30 | be779cef54498793c71bf7a677669f665874dac08141c43c4532bf08d22c5946 |
The potential for harm from doing the dexamethasone suppression test is low and relates mainly to unnecessary investigations for Cushing syndrome. Therefore, the panel concluded that the balance of effects probably favors the intervention and that the test is feasible, accessible, and cost-effective. | 55 | 30 | 30 | 31dc098a4d2d8b1decba36d23a7f3887f816da039be519be3fe61fd5597608c5 |
Comments Individuals with adrenally mediated, overt Cushing syndrome and unilateral adrenal adenoma may proceed to surgery, with - out AVS, to remove the source of excess cortisol. Research Considerations Current gaps in knowledge call for further research in the fol - lowing areas: | 56 | 30 | 30 | 0a6355cf78e6e51670f912f6e6cd9a9cb9ae8be20212225272a8353c0d0aaa7e |
• Determining the prevalence of mild autonomous cortisol excess, as indicated by an abnormal 1-mg dexamethasone suppression test, in individuals with PA who do not have an adrenal adenoma • Evaluating the role of adrenal and peripheral vein meta - nephrine for assessing selectivity and lateralization with the goal of i... | 155 | 30 | 30 | 210488ee580f599e2487ba005843aa12318ba9649c6fbda5fd018d4c2d66c2d5 |
Spironolactone vs Other Mineralocorticoid Receptor Antagonists Medical therapy for primary aldosteronism (PA) will likely become the central issue in PA care over the next decade as PA becomes more widely recognized ( 209 ). | 50 | 30 | 30 | 53bcfedacf386a15e6fd266c8b19f1b29359ea4013770b5c318f48b68d780fd1 |
Modern PA series already show that, with expanded PA screening, an increasing majority of PA cases are nonsurgical, bilateral adrenal 2482 The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. | 43 | 30 | 30 | 6714b007755e2c41df2ace3c8e5fe17a99b46a9b038235cd06ff48e4377a0d65 |
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hypersecretory states ( 210 ). Further, lack of access to AVS ne - cessitates guidance on specific MRA selection. Question 9. Should spironolactone vs other mineralocortic - oid receptor antagonists be used for primary aldosteron - ism–specific medical therapy? | 62 | 31 | 31 | be346e9e67911d31e5692aefddceaaeccaac498d9784016fae1ba2ddebc82b5a |
Recommendation 9 In individuals with primary aldosteronism (PA) receiv - ing PA-specific medical therapy, we suggest spironolac - tone over other mineralocorticoid receptor antagonists (MRAs) due to its low cost and widespread availability (2 | ⊕ OOO). | 63 | 31 | 31 | 9a752123230cc34a69ebc51ba0ec0dda3fc0c6e17450d2900d373bbc17855249 |
Technical remarks: • The recommendation is driven by the availability and low cost of spironolactone vs other MRAs; however, all MRAs, when titrated to equivalent po - tencies, are anticipated to have similar efficacy in treating PA. | 51 | 31 | 31 | cab1b5e3f815e9085542d4d861cf3601b6584bb93566e5440776b31959b661c9 |
MRAs with greater mineralocorticoid receptor (MR) specificity and fewer androgen/ progesterone receptor-mediated side effects may be preferred. • When initiating MRAs, consider hypertension se - verity for dosing and potential discontinuation of other antihypertensive medications ( Fig. | 60 | 31 | 31 | b83223165a40f6e3a89269fdee527d27d53ffc3bf0903654db0f5c76e8393b96 |
• Monitor potassium, renal function, renin (concentra - tion or activity), and blood pressure (BP) response during follow-up to guide MRA dose titration. Summary of the Evidence The meta-analysis results, a detailed summary of the evidence and Evidence to Decision (EtD) tables can be found online at https:/ /guidelines... | 91 | 31 | 31 | fbc31ef1a748d5f6bd8cd387781924f87d9e7e36a5de3354648b5aba8ea4b27d |
Benefits and Harms The panel voted for the following patient-important outcomes for Question 9 decision making: 1) percent of individuals achieving BP control, 2) number of antihypertensive agents, 3) dosage of antihypertensive agents, 4) systolic BP (SBP) level, 5) control of hypokalemia, 6) quality of life (QOL), and... | 86 | 31 | 31 | f725db347a27c6035e17307927cf864c4af10bd1ceee29e959e214c6e3dd4140 |
The systematic review ( 53 ) identified 3 relevant randomized controlled trials (RCTs) ( 122 , 211 , 212 ), (n = 229) and 1 com - parative observational study (n = 188) with an equal distribu - tion of women and men ( 29 ). | 57 | 31 | 31 | 13ac3a92cac18923c462acb4379c2bd061981f6644a95c270ac38e2bc6cc43d7 |
The meta-analysis concluded that eplerenone, compared with spironolactone, was associated with a higher number of antihypertensive agents and dosage of antihypertensive agents. | 40 | 31 | 31 | ac9b50cebccbd4ab8045c1aeaf5e9ae0f75e8181ffa4c71322ee52339ceeb838 |
However, the doses of the medications were not renin-guided to ensure dose-equivalent MR blockade. There were no statistically significant differences in achieving BP control, control of hypokalemia, and SBP level. | 45 | 31 | 31 | f64aeb1eed64b1938432251a03be2f3200032c3a760ea1980a91ee644dfcc6dd |
Data from the direct evidence were insufficient to inform on broad issues of ad - verse events or QOL, although increased female breast pain and male gynecomastia were reported with spironolactone use. | 43 | 31 | 31 | ce39ac0ce2e095fa37e3b24ed9a4522965547f92336f5266ee2559bd676aa029 |
After completion of the systematic review, but prior to publication of these guidelines, a new study comparing short-term finerenone and low-dose spironolactone in PA was published demonstrating comparable blood pressure – lowering efficacy and effects upon serum potassium and renin concentration ( 213 ). | 57 | 31 | 31 | 5ee8b57e1ae4a166a8f51335817c23d1817f6caf8c37b03ad89ddc23fb86261b |
Spironolactone has far greater ability to block androgen ac - tion and affect progesterone action than does eplerenone. As this may be relevant to the issue of individual tolerability, the Guideline Development Panel (GDP) considered indirect evi - dence in the form of studies reporting use other than for a PA indicati... | 72 | 31 | 31 | c357e89a03646d0131b0baaad9a13e748b84e8985263fe5036ad6499e9652cc3 |
Two systematic reviews/meta-analyses were found that compared spironolactone with eplerenone or canrenone ( 214 , 215 ). One meta-analysis of 14 studies and including 3745 individuals using spironolactone for non-PA indications showed a male gynecomastia incidence rate of 7.9% vs 0.6% among placebo users (OR: | 80 | 31 | 31 | faad465ff311b3e9f4be5c20e53e5d1d203350bb299eda02eaaabc0f6cb525d3 |
8.39 [5.02-13.99]), although this was still less than that observed in users of anti-androgens or ris - peridone ( 214 ). Among users of MRAs or placebo for heart fail - ure, spironolactone had a relative odds of 8.44 (3.9-18.2) vs eplerenone 0.77 (0.31-1.88) for male gynecomastia ( 215 ). | 99 | 31 | 31 | 2acb7208d5156bae1783df7406edbf893af73176194d9b12f8d7e771534d28fc |
Evidence to Decision Factors • Studies specifically comparing spironolactone vs other MRAs in medical PA treatment were few in number, small in size, and judged to be low quality. All used surrogate outcomes (eg, BP changes or serum potassium levels), typically ascer - tained after short treatment intervals. | 62 | 31 | 31 | 49ab341f1d1ef0297864e3b4001febc0e96516f6c0fa896baf487a8a873f11f5 |
Heterogeneity and un - balanced baseline characteristics in study PA individuals (severe vs mild or mixed PA, lateralizing vs bilateral PA, hypo- or eukalemia) limited the interpretability of meta- analysis. | 45 | 31 | 31 | c9cb3ca322e90e58eea5adf98d28311a411dfe1c7b60372d276ba8afdd3e6fb1 |
MR-blocking potencies of various MRA agents were not routinely built into treatment protocols, and non - equivalent drug doses were sometimes compared. Dose titra - tion was not uniformly part of the study designs, and, even if so, titration schemes generally did not reflect modern (ie, renin-guided) titration paradigm... | 74 | 31 | 31 | a7c25de699ab101c2d0b0c16c500f94f8f36fa63e6f7c108cef7b11030ad811b |
• In order to proceed despite the evidence gaps, the GDP agreed to make the following 5 assumptions as part of the EtD process: ⚬ Each MRA, titrated appropriately, by blocking the MR, likely has an equal chance of eventually achieving the same degree of BP and potassium control in individ - uals with PA. | 68 | 31 | 31 | a9e9f5d3ed904680e49dbacf2a359491e5500ee95c1fd766356d20ce5eced7aa |
⚬ Each MRA, once titrated to equivalent MR blockade, likely has an equal chance of permitting discontinu - ation of other antihypertensives. ⚬ Rates of adverse events may differ between the MRAs. ⚬ QOL differences may be explained by adverse event rates. | 63 | 31 | 31 | c17382d29a2e7d5801e817e0b2c485d5405c7754876572eb65ee4c0606ecf478 |
⚬ QOL differences may exist outside of adverse event oc - currences but would need appropriately designed head-to-head comparisons of sufficient duration to detect. • Expected costs of medical therapy were considered in de - tail by the GDP, although high-quality cost-effectiveness modeling data in PA specifically is s... | 70 | 31 | 31 | 99deeca00b30fe9a0a9113c5a24422719bc464b93c144cc9521ffb290181e586 |
• It was acknowledged that available studies focused on ex - pected costs would not necessarily translate to all individu - als and countries, even among high-resource health systems. • It was also noted that modeling cost-effectiveness in a PA setting would be highly complex and difficult to perform without high-quali... | 77 | 31 | 31 | e57b1c15df4e4d8233e37403174b05688963cc210b3d9166af819afb8b7616e8 |
The Journal of Clinical Endocrinology & Metabolism , 2025, Vol. 110, No. 9 2483 Downloaded from https://academic.oup.com/jcem/article/110/9/2453/8196671 by University of Wisconsin System user on 20 February 2026 | 62 | 31 | 31 | 80506c2b509b18042b4a99b8c3015ed2771175d34b7ff4f2cea13fa4f3bd0262 |
• Additionally, with PA diagnosed at young or middle ages, a lifetime model must include very long-term costs of ther - apy balanced against the long-term cost trajectory of re - duced disease burden. | 43 | 32 | 32 | cead323670dc189c2bf027d0336e72f69ce704c17e2b882c06d0d9d7f0715bf7 |
• Nonetheless, attempts at cost estimates in other cardiovas - cular conditions ( 216-218 ) consistently demonstrate markedly lower costs for spironolactone vs eplerenone; newer MRA drugs will likely have the highest costs. | 49 | 32 | 32 | dfcf86ef3ac579e3bbb0c8bdf32b27850e7b2ef55f12229b0251d32c23d8af0f |
• In cost-modeling studies of PA diagnosis and therapy, giv - en the lifelong requirement for MRA treatment in those who do not receive surgery, the cost of medication is ex - pected to rapidly dominate the cost inputs for all but the oldest individuals. | 54 | 32 | 32 | d81d2d07ab2ef3122d9345389121b9dae4a21192dd464ba23044056017afc76e |
• The GDP made specific note of the individual concerns about tolerability and side effect risk, recognizing the im - portant role of individual preference in choice of MRA, beyond cost considerations alone. Justification for the Recommendation Although legitimate individual concerns about tolerability of spironolacton... | 89 | 32 | 32 | c01ee0ab8102b2d6eab6d0d5d063af2843c40b3e910d1bfa963fc8edcc9dd5b8 |
Cost considerations or risk of unwanted anti-androgen effects may be secondary concerns and are likely highly significant when comparing spironolactone vs other MRAs. Shared decision making with individual patients allows for use of a non- spironolactone MRA in PA treatment where desired. | 58 | 32 | 32 | 7d014cc1f503d3dbdf80c7897d3bc59ce867e5ff369453a37a120f106ab3dd5f |
Comments A recent international consensus document regarding the spe - cific targets and means of implementing optimized MRA ther - apy has been published ( 85 ). As new evidence for new MRAs in PA emerges, recommendations may require updating, al - though major differential cost considerations may continue to dominate... | 61 | 32 | 32 | 862c73af0dca915285fe6c050336f1716600eb20ec9306cb24d193f9d8b73178 |
Research Considerations Current gaps in knowledge call for further research in the fol - lowing areas: • Evaluating aldosterone synthase inhibitors with appropri - ately designed PA-specific research studies to determine their optimal position within a PA treatment framework; ongoing trials of MRA drugs such as esaxere... | 181 | 32 | 32 | 86e6656bf0b7f4a910d92517476b2d7a81d25be801c66590bd4864b5e624342b |
These demands may challenge health care systems with limited resources, where access to speci - alized equipment, expertise, and follow-up care could be uneven. In such settings, pathways involving direct medical treatment, such as initiating MRAs based on screening results alone, may be considered when further testing... | 63 | 32 | 32 | 22f3a98ca8e6477af49a7abcaad0184696f0f484e0d83c300b39f88d9b05bfa7 |
Variability in resources across settings highlights potential in - equities, with rural and low-resource areas facing the greatest barriers. Practical adaptations, such as simplified diagnostic algorithms or regional hubs for specialized care, could miti - gate these challenges. | 49 | 32 | 32 | 3e4f9261074042373efaf169fd61eba8db3f7ae149a4fa6defcc820b4271b157 |
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