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Aldosterone synthase inhibitors in hypertension: current status and future possibilities

Aldosterone synthase inhibitors in hypertension: current status and future possibilities The renin-angiotensin aldosterone system is a critical mechanism for controlling blood pressure, and exerts most of its physiological effects through the action of angiotensin II. In addition to increasing blood pressure by increasing vascular resistance, angiotensin II also stimulates aldosterone secretion from the adrenal gland. Aldosterone acts to cause an increase in sodium and water reabsorption, thus elevating blood pressure. Although treatment with angiotensin converting enzyme inhibitors initially lowers circulating aldosterone, with chronic treatment aldosterone levels increase back to baseline, a phenomenon termed aldosterone escape; aldosterone blockade may therefore give added value in the treatment of hypertension. The first mineralocorticoid receptor antagonist developed was spir- onolactone, but its use has been severely hampered by adverse (notably oestrogenic) effects. The more recently developed mineralocorticoid receptor antagonist eplerenone exhibits a better adverse effect profile, although it is not devoid of effects similar to spironolactone. In addition, aldosterone activates non-genomic receptors that are not inhibited by either eplerenone or spironolactone. It is believed that deleterious organ remodelling is mediated by aldosterone via such non-genomic pathways. A new class of drugs, the aldosterone synthase inhibitors, is cur- rently under development. These may offer a novel therapeutic approach for both lowering blood pressure and preventing the non-genomic effects of aldosterone. Here, we will review the cardiovascular effects of aldosterone and review the drugs available that target this hormone, with a particular focus on the aldosterone synthase inhibitors. Keywords Clinical studies, hypertension, cardiology, remodeling Introduction First line treatment of hypertension involves lifestyle Hypertension is one of the most important preventable and dietary changes. If these measures are not effect- causes of premature morbidity and mortality in the ive, drug therapy is commenced. There are a wide var- developed world. It is a major risk factor for ischaemic iety of antihypertensive drugs available including and haemorrhagic stroke, myocardial infarction, heart angiotensin converting enzyme inhibitors (ACEi), failure, chronic kidney disease and cognitive decline. angiotensin II receptor blockers (ARB), calcium chan- Most cases of hypertension have no known cause and nel blockers (CCB), beta blockers, alpha blockers and are termed essential hypertension. Secondary causes of diuretics. A number of national and international hypertension account for approximately 10% of cases, guidelines exist for the treatment of hypertension, and treatment of secondary hypertension generally with some differences between them. The seventh involves treating the underlying cause. Whatever the Joint National Committee on Prevention, Detection, aetiology, it is clear that controlling high arterial pres- sure improves prognosis and is an important compo- School of Medicine, King’s College London, London, UK nent of primary prevention of cardiovascular disease. Corresponding author: Persistent hypertension can lead to left ventricular Albert Ferro, British Heart Foundation Centre for Research Excellence, hypertrophy and remodelling of resistance arteries, Cardiovascular Division, King’s College London, 150 Stamford Street, both of which are associated with adverse cardiovascu- London SE1 9NH, UK. lar outcomes. Email: albert.ferro@kcl.ac.uk XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] 2 Journal of the Royal Society of Medicine Cardiovascular Disease 0(0) Evaluation and Treatment of High Blood Pressure cur- of a CCB and ACEi or ARB, with the further addition rently recommends thiazide diuretics should be used as of a diuretic if control is still not achieved. an initial therapy in most patients (although new guide- In approximately 10% of patients with hyperten- lines are due to be released soon); if the blood pressure sion, a combination of three antihypertensives (typic- remains uncontrolled (>160/100 mmHg), then a two- ally diuretic, CCB plus ACEi or ARB) is not effective at drug combination with a thiazide diuretic and either a controlling blood pressure. In these cases of ‘resistant CCB, ACEi or ARB is advocated. Guidance from the hypertension,’ the aldosterone antagonist spironolac- World Health Organisation dictates that the choice of tone is often added to the treatment regimen. antihypertensive should be based on cost effectiveness Aldosterone antagonism with spironolactone, or and any specific indications such as the particular bene- indeed with the newer drug eplerenone, has been fits of ACEi or ARBs in the context of renal disease. In shown to be effective at lowering blood pressure in England and Wales, the latest National Institute for such patients and has a range of beneficial cardiovas- 10–12 Health and Care Excellence (NICE) guidelines recom- cular effects, thus highlighting the potential bene- mend starting drug treatment in those with stage 1 fits of targeting aldosterone in the management of hypertension (>140/90 mmHg) with one or more add- resistant hypertension, especially where other cardio- itional risk factors (such as diabetes, end-organ damage vascular risk factors may coexist. and renal disease) and treating anyone with stage 2 hypertension (>160/100 mmHg); in Caucasian patients The importance of aldosterone within the under 55 years of age, an ACEi or ARB is advocated, renin angiotensin aldosterone pathway whilst in people of African/Caribbean origin and all those over 55, a CCB is recommended as these patients The renin angiotensin aldosterone system (RAAS; generally have lower plasma renin. If blood pressure is Figure 1) plays an essential role in blood pressure con- still not controlled, NICE recommends a combination trol through regulating fluid and electrolyte balance. Figure 1. The renin angiotensin aldosterone system. Also shown are the sites of action of ACEi, ARB, aldosterone synthase inhibitor and MR antagonist drugs. XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] Hargovan and Ferro 3 Angiotensin II is the main effector of the RAAS, acting In addition to its genomic effects, aldosterone is on the type I angiotensin II receptor resulting in thought to exert non-genomic actions, which are increased blood pressure by a combination of vasocon- mediated via effects on protein kinase C, intracellular striction, increased cardiac output, vascular remodel- calcium and cyclic adenosine monophosphate. It has ling and increased aldosterone secretion. been proposed that non-genomic effects could contrib- Angiotensin II increases the synthesis of aldosterone ute to vascular smooth muscle cell hypertrophy, vascu- by upregulating the CYP11B2 gene, which encodes the lar fibrosis and interstitial fibrosis of the kidney enzyme aldosterone synthase, in the zona glomerulosa alongside genomic effects of aldosterone, which also of the adrenal cortex. Aldosterone synthase expression mediate cardiovascular fibrosis. This provides a pos- 20,21 is also stimulated by potassium and adrenocortico- sible additional target for therapeutic intervention. 14,15 trophic hormone (ACTH). Aldosterone plays an important role in electrolyte Aldosterone antagonists homeostasis, through acting on mineralocorticoid receptors (MR) in the cortical collecting ducts of the Although prevention of angiotensin II generation or kidney to increase expression of sodium channels, lead- action would be expected to prevent the secretion of ing to sodium and water reabsorption which is coun- aldosterone, this is not universally the case. For exam- tered by potassium loss. The resultant increase in ple, the randomised evaluation of strategies for left ven- plasma volume leads to a rise in blood pressure. The tricular dysfunction (RESOLVD) trial showed that MR is a nuclear transcription factor that binds hor- suppression of the RAAS system with an ACEi and mone response elements and increases transcription of an ARB did not suppress aldosterone secretion in the 16 22 sodium channels. long term. This phenomenon has been described as The role of aldosterone in hypertension had first ‘aldosterone escape.’ In consequence of this, inhibiting been recognised in 1954 by Conn and Louis, when aldosterone exerts an additive effect to inhibiting angio- they cured a case of hypertension by removal of an tensin II as regards controlling blood pressure. It is adrenal adenoma which secreted excess aldosterone. believed that use of conventional agents that target The largest study to date has found that primary aldos- the RAAS leads to an upstream accumulation of teronism accounts for 11% of patients with hyperten- renin, which contributes to the rise in aldosterone sion, although this figure may vary according to levels both through overcoming RAAS inhibition by ethnicity and comorbidities. the law of mass action and by generating aldosterone Aldosterone also plays an important role in hyper- through alternative pathways that bypass the classical tension in the absence of primary aldosteronism. It has RAAS. been demonstrated that up to 15% of hypertensive Spironolactone was the first MR antagonist to be patients have an abnormally high aldosterone / renin developed, and is used for the treatment of hyperten- ratio; and in patients with resistant hypertension, this sion, primary hyperaldosteronism and peripheral proportion rises to around 25%. Thus, higher 24-hour oedema associated with cardiac failure and other urinary aldosterone levels have been found in patients pathologies associated with secondary aldosteronism. with resistant hypertension as compared to patients Unfortunately, spironolactone is not well tolerated, with controlled hypertension. mainly due to its lack of specificity for the MR: it The effects of aldosterone are more widespread than also binds to progesterone and androgen receptors, simply regulating sodium and potassium levels. leading to menstrual irregularities in women and Mineralocorticoid receptors are found in a large sexual dysfunction with painful gynaecomastia in range of tissues including adipose, cardiac myocytes, men. This adverse event profile prompted the search brain and vascular endothelium, cardiac fibroblasts for better tolerated MR antagonists. This led to the and vascular smooth muscle cells. Aldosterone acti- development of eplerenone, a compound that exhibits vation of mineralocorticoid receptors leads to upregu- reduced affinity for sex steroid receptors and so is less lation of NADPH oxidase and thereby increased prone to cause the sex hormone-related adverse effects production of reactive oxygen species (ROS). The gen- of spironolactone. However, as with spironolactone, eration of ROS leads to reduced bioavailability of nitric electrolyte imbalances in particular hyperkalemia can oxide, which is associated with impaired relaxation of occur in up to 5% of patients, especially in the pres- vascular smooth muscle cells, thereby leading to ence of renal dysfunction and in combination with increased peripheral vascular resistance and higher other potassium-retaining drugs such as ACEi or blood pressure. Furthermore, lower nitric oxide levels ARB. Eplerenone also exhibits reduced affinity for the are associated with endothelial dysfunction and MR compared to spironolactone. increased cell adhesion molecule expression, which Non-steroidal MR antagonists are currently being increase the risk of atherosclerosis. developed, and these may offer advantages over XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] 4 Journal of the Royal Society of Medicine Cardiovascular Disease 0(0) spironolactone and eplerenone. BAY94-8662 has been reduction in mortality. It is possible that the beneficial shown to be more selective for the mineralocorticoid effects of mineralocorticoid blockade seen in this study receptor than spironolactone and has greater affinity were due to changes in cardiac structure rather than than eplerenone. In a recent phase 2 study, BAY 94- blood pressure. From such evidence it can be inferred 8862 was shown to be safe and tolerable in patients that aldosterone is linked to organ damage, and that with chronic heart failure and mild chronic kidney dis- inhibiting its action provides added benefit over and ease. Furthermore, BAY 94-8862 was shown to be as above lowering of blood pressure. effective as spironolactone at reducing biomarkers of heart failure and CKD with a better adverse effect Aldosterone synthase inhibitors profile. Although spironolactone and eplerenone effectively lower blood pressure, they can cause reactive increases Aldosterone inhibition and end-organ in circulating renin and aldosterone levels, reducing the damage effectiveness of treatment. Furthermore, experimental As mentioned earlier, inhibition of aldosterone gives data suggest that some of the deleterious effects of rise to beneficial effects on end-organ function. This aldosterone may occur through non-genomic pathways, was indeed proved to be the case in the 4E (eplerenone, independently of stimulation of the MR. If non- enalapril, eplerenone and enalapril) trial, a double blind genomic pathways do contribute importantly to the randomised 9-month-long trial in patients with hyper- effects induced by aldosterone, drugs which inhibit tension and left ventricular hypertrophy. In this trial, aldosterone synthase would potentially offer an advan- eplerenone was equivalent to enalapril at reducing tage over MR antagonists in preventing activation of blood pressure, and the combination of enalapril and both genomic and non-genomic pathways. eplerenone caused a greater reduction in blood pressure Aldosterone production is largely controlled by than either monotherapy. Furthermore, left ventricular regulation of transcription of the CYP11B2 gene mass was reduced to the greatest extent by the combin- which encodes aldosterone synthase. This enzyme cata- ation therapy, followed by treatment with eplerenone lyses the final three rate-limiting steps of aldosterone alone. Treatment with enalapril alone caused the least synthesis (Figure 2). It is located in the mitochondria reduction in left ventricular mass. This study demon- and is part of the cytochrome P450 family. The syn- strated that eplerenone is highly effective at reducing thesis of aldosterone and cortisol are closely linked. target end-organ damage associated with hypertension, Cortisol production occurs in the zona fasiculata of and more complete blockade of the RAAS using an the adrenal cortex, the final step of cortisol synthesis ACEi and eplerenone combined provided the greatest involving the enzyme 11-b-hydroxylase which is degree of protection. It is important to note, however, encoded by the CYP11B1 gene. The CYP11B1 and that the short duration of this study means that the CYP11B2 gene are both located on the short arm extrapolation of long-term patient outcomes was not of chromosome 8. Transcription of the CYP11B1 gene possible. is stimulated by ACTH and that of the CYP11B2 gene Aldosterone is also linked to the pathogenesis of by angiotensin II and potassium. The similarity of renal damage. Observational studies have shown that aldosterone synthase and of 11-b-hydroxylase has ren- there is a correlation between aldosterone levels and dered it difficult to find a specific a specific inhibitor proteinuria in patients with diabetic nephropathy; and that selectively targets aldosterone synthase. clinical studies have shown improvements in protein- uria with eplerenone treatment. Preclinical studies of aldosterone synthase inhibition The role of aldosterone in heart failure is well estab- lished. The randomized aldactone evaluation study Fadrozole and its dextroenantiomer FAD 286, which (RALES) showed a 30% reduction in mortality in have inhibitory properties against aldosterone synthase, patients with severe heart failure when treated with have been experimentally tested preclinically but have 28 32–34 spironolactone in addition to usual therapy. The never been investigated in patients. In spontan- Eplerenone post acute MI heart efficacy and survival eously hypertensive rats, FAD286 dose dependently study (EPHESUS) trial showed that addition of epler- reduced urine and plasma aldosterone levels; however, enone to standard treatment reduced hospital readmis- in combination with spironolactone it caused severe sion by 23% in patients who had experienced an dehydration and hyperkalemia, thus highlighting the acute myocardial infarction complicated by left ven- potential danger of complete aldosterone inhibition tricular dysfunction. In this trial, eplerenone doses using combination therapies. of 25 mg daily, which had only a minor effect on In transgenic mice overexpressing human renin and blood pressure, were associated with a significant aldosterone, FAD286 reduced mortality, prevented XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] Hargovan and Ferro 5 Figure 2. Schematic of adrenal steroid biosynthesis. cardiac hypertrophy and matrix deposition in the heart aldosterone synthase, produce dose-dependent reduc- and kidney. However, it was not as effective as an ARB tions in aldosterone levels, reduce blood pressure and at reducing blood pressure. prevent end-organ damage. However, aldosterone syn- In rat models of congestive heart failure, FAD286 thase inhibition prevented end-organ damage to a simi- showed beneficial haemodynamic effects and improved lar extent as mineralocorticoid receptor antagonism, left ventricular function and remodelling to a similar suggesting that aldosterone does in fact mediate end- extent as spironolactone. organ damage via mineralocorticoid receptor depend- In spontaneously hypertensive rats, reduction in ent mechanisms. On the other hand, the discordant myocardial fibrosis by the two enantiomers of fadro- enantioselectivity of fadrozole on cardiac fibrosis, des- zole were compared to a mineralocorticoid recep- pite equal effects on circulating aldosterone levels, tor antagonist. At high doses, both the S and the argues for an effect of this drug which may be non- R enantiomers of fadrozole lowered plasma aldoster- aldosterone-mediated. Further studies are required to one levels to similar extents; but interestingly, only dissect out any possible effects of this drug which are R-fadrozole reduced cardiac fibrosis (by 50%) whereas not exerted through modulating aldosterone synthesis. S-fadrozole had no such effect. This raises the question The translational potential of FAD286 is also ham- of whether the antifibrotic effects of this drug are truly pered by the fact that it lacks selectivity for aldosterone mediated via reduction in plasma aldosterone or synthase, since it also inhibits 11-b-hydroxylase to a through other as yet unrecognised mechanisms. large extent; this leads to inhibition of cortisol synthesis In uninephrectomised rats on a high salt diet treated secondary to ACTH or stress. This lack of selectivity is with angiotensin II, both FAD286 and spironolactone likely to reduce the potential clinical usefulness of reduced blood pressure. After 8 weeks, FAD286 was FAD286. associated with a reduction in plasma aldosterone levels whereas spironolactone was associated with Clinical studies of aldosterone synthase inhibition increased plasma aldosterone. Nevertheless, both FAD286 and spironolactone reduced renal and cardiac The success of FAD286 in preclinical studies led to the hypertrophy and interstitial fibrosis to a similar development of LCI699, which has greater selectivity extent. for inhibition of CY11B2 over CY11B1, thereby In summary, preclinical studies of FAD286 have having less of an influence on cortisol. LC1699 is the generally been positive, although they have raised new first orally active aldosterone synthase inhibitor that questions. The drug has been shown to inhibit has been tested in humans. XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] 6 Journal of the Royal Society of Medicine Cardiovascular Disease 0(0) Phase 1 study. In a double blind, placebo controlled trial 1.0 mg daily had suppression of ACTH stimulated in 12 healthy normotensive subjects, LCI699 at doses of release of cortisol, indicating partial inhibition of 11- 0.5–3.0 mg once daily caused a dose-dependent b-hydroxylase (CYP11B1) although it did not reduce decrease in plasma and urine aldosterone levels. It did plasma cortisol concentrations and no patients devel- not affect cortisol levels at lower doses and was well oped signs of hypocortisolism. The most frequently tolerated. However, at 3 mg daily selectivity was lost occurring adverse effects were headache, dizziness and and it blunted cortisol responses to ACTH, and also nasopharyngitis, which were similar in the LCI699 and caused signs of hypoaldosteronism (postural tachycar- placebo groups. Hyperkalemia occurred in 3% of dia, mild hyponatraemia and reduced body weight). patients in both the LCI699 and placebo groups. The These results supported further evaluation of compound was safe and well tolerated. LC1699. A study by Andersen et al set out to find the max- imum tolerated dose of LCI699 with respect to corti- Phase 2 studies. In a single blind, proof of concept phase sol suppression by ACTH. In all, 63 patients were 2 a study, 14 hypertensive patients with primary aldos- randomised in a double-blind fashion to either pla- teronism received LCI699 0.5 mg daily for the first two cebo or various doses of LCI699. The trial found weeks followed by 1 mg daily for a further two weeks, dose-dependent reductions in both systolic and dia- and finally placebo for one further week. Plasma stolic blood pressures by LCI699. The maximum tol- aldosterone levels were reduced by up to 80% in a erated dose was found to be 1.3 mg once daily. dose-dependent manner with treatment, and this was LCI699 had no serious adverse effects and no patients accompanied by dose-dependent increases in deoxycor- developed signs or symptoms of adrenal ticosterone (the aldosterone precursor), confirming the insufficiency. inhibition of aldosterone synthase. The inhibitory In a study of 155 patients with treatment-resistant effects on aldosterone synthase were maintained hypertension, patients were randomised in a double throughout the study, with no escape phenomena and blind fashion to receive over 8 weeks either placebo, no rebound effect seen after treatment was with- eplerenone 50 mg twice daily or varying doses of drawn. Plasma potassium increased by a mean of LCI699 (0.25 mg twice daily, 0.5 mg once daily, 1 mg 0.73 mmol/L and there was a mild increase in plasma once daily or 1 mg twice daily). Eplerenone gave rise renin concentration. Although plasma cortisol levels to a significant reduction in systolic and diastolic were unaffected, there was evidence of inhibition of blood pressure (9.9 and 2.9 mmHg, respectively). 11-b-hydroxylase as both plasma ACTH and 11-dehy- Surprisingly there was no significant reduction in droxycortisol (the precursor to cortisol) were raised. either systolic or diastolic blood pressure with any Furthermore, all patients had a blunted cortisol dose of LCI699. However, LCI699 did suppress response to ACTH. The lack of selectivity for plasma aldosterone and increase deoxycorticosterone CYP11B1 and CYP11B2 is consistent with preclinical levels in a dose-dependent manner. The reasons for studies using fadrozole. Additionally, ambulatory sys- this discrepancy are not clear, and the findings are tolic blood pressures were modestly reduced by contradictory to those of the studies by Calhoun 4 mmHg over 4 weeks. It was concluded that up to et al. and Andersen et al. This merits further evalu- 1 mg daily of LC1699 was safe and well tolerated, and ation in larger trials and suggests that aldosterone syn- effectively reduced plasma aldosterone levels as well as thase inhibition may be of clinical use only in partially correcting hypokalaemia in patients with pri- combination with other antihypertensive agents; or mary hyperaldosteronism. at any rate may be more useful in reducing end- Calhoun et al. recently carried out a randomised organ damage by aldosterone rather than in lowering controlled, double blind phase 2 trial, in which 534 blood pressure. patients with mild to moderate primary hypertension The most recent trial compared aldosterone synthase received LCI699 0.25–1 mg daily, eplerenone 50 mg inhibition using LCI699 with mineralocorticoid recep- twice daily or placebo. After 8 weeks, there was a tor blockade in patients with primary hyperaldosteron- dose-dependent reduction of mean systolic blood pres- ism. In addition to usual medications, patients were sure with LCI699. The daily 1.0 mg dose significantly treated with LC1699 for 30 days followed by placebo reduced systolic blood pressure by a mean of washout for 1 week followed by another 30 days of 12.6 mmHg, while eplerenone 50 mg twice daily reduced treatment with eplerenone. Thirty days of treatment systolic blood pressure by a mean of 13.8 mmHg, com- with eplerenone reduced 24-hour ambulatory blood pared with placebo; 24-hour mean ambulatory diastolic pressure by 5 mmHg more than LCI699; however, and systolic blood pressure were reduced to similar LCI699 was associated with a 75% decrease in extents by eplerenone and LCI699 1.0 mg daily after 8 plasma aldosterone whilst eplerenone increased aldos- weeks. Twenty percent of patients receiving LCI699 terone levels by 89%. XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] Hargovan and Ferro 7 protection in hypertensive patient populations may Conclusions pave the way for a broader use of aldosterone blockers, The development of LCI699 has allowed assessment of and in the future possibly also of aldosterone synthase the benefits and safety of inhibiting aldosterone synthe- inhibitors, especially if more selective agents can be sis in hypertensive patients. Unfortunately, the lack of developed. selectivity of LCI699 at higher doses (above 3 mg daily) giving rise to inhibition of 11-b-hydroxylase Guarantor (CYP11B1) and alteration of the glucocorticoid axis Albert Ferro limits the dose that can be used. It is unlikely that LCI699 will supplant mineralocorticoid receptor block- Contributorship ers clinically as the latter are more effective at lowering Milan Hargovan performed the literature search. Milan blood pressure. The development in due course of a Hargovan and Albert Ferro wrote the paper second generation of more selective blockers of aldos- terone synthase should make it possible to test the value Funding of this approach, hopefully to achieve greater reduc- tions in blood pressure without affecting the gluco- This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. corticoid axis. It should be noted that inhibition of aldosterone synthesis is not free of risks. As with mineralocor- Conflict of interest ticoid receptor blockade, aldosterone synthase inhibi- None declared. tors are likely to cause hyperkalemia and hyponatraemia. Furthermore, their long-term effect References on kidney function is not known. 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Safety and toler- aldosterone synthase inhibition on aldosterone and corti- ability of the novel non-steroidal mineralocorticoid recep- sol in patients with hypertension: a phase II, randomized, tor antagonist BAY 94-8862 in patients with chronic double-blind, placebo controlled, multicenter study. heart failure and mild or moderate chronic kidney J Clin Hypertens 2012; 14: 580–587. XML Template (2014) [4.2.2014–10:50am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] Hargovan and Ferro 9 41. Karns AD, Bral JM, Hartman D, et al. Study of aldos- 43. Bertagna X, Pivonello R, Fleseriu M, et al. Patients with terone synthase inhibition as an add-on therapy in resist- Cushing’s disease achieve normal urinary cortisol with ant hypertension. J Clin Hypertens 2013; 15: 186–192. LCI699, a potent 11b-hydroxylase inhibitor: preliminary 42. Amar L, Azizi M, Menard J, et al. Sequential comparison results from a multicenter, proof-of-concept study. of aldosterone synthase inhibition and mineralocorticoid Endocrine Abstracts 2012; OR012. blockade in patients with primary aldosteronism. J Hypertens 2013; 31: 624–629. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JRSM Cardiovascular Disease Pubmed Central

Aldosterone synthase inhibitors in hypertension: current status and future possibilities

JRSM Cardiovascular Disease , Volume 3 – Feb 5, 2014

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Pubmed Central
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© The Author(s) 2014
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2048-0040
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2048-0040
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10.1177/2048004014522440
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Abstract

The renin-angiotensin aldosterone system is a critical mechanism for controlling blood pressure, and exerts most of its physiological effects through the action of angiotensin II. In addition to increasing blood pressure by increasing vascular resistance, angiotensin II also stimulates aldosterone secretion from the adrenal gland. Aldosterone acts to cause an increase in sodium and water reabsorption, thus elevating blood pressure. Although treatment with angiotensin converting enzyme inhibitors initially lowers circulating aldosterone, with chronic treatment aldosterone levels increase back to baseline, a phenomenon termed aldosterone escape; aldosterone blockade may therefore give added value in the treatment of hypertension. The first mineralocorticoid receptor antagonist developed was spir- onolactone, but its use has been severely hampered by adverse (notably oestrogenic) effects. The more recently developed mineralocorticoid receptor antagonist eplerenone exhibits a better adverse effect profile, although it is not devoid of effects similar to spironolactone. In addition, aldosterone activates non-genomic receptors that are not inhibited by either eplerenone or spironolactone. It is believed that deleterious organ remodelling is mediated by aldosterone via such non-genomic pathways. A new class of drugs, the aldosterone synthase inhibitors, is cur- rently under development. These may offer a novel therapeutic approach for both lowering blood pressure and preventing the non-genomic effects of aldosterone. Here, we will review the cardiovascular effects of aldosterone and review the drugs available that target this hormone, with a particular focus on the aldosterone synthase inhibitors. Keywords Clinical studies, hypertension, cardiology, remodeling Introduction First line treatment of hypertension involves lifestyle Hypertension is one of the most important preventable and dietary changes. If these measures are not effect- causes of premature morbidity and mortality in the ive, drug therapy is commenced. There are a wide var- developed world. It is a major risk factor for ischaemic iety of antihypertensive drugs available including and haemorrhagic stroke, myocardial infarction, heart angiotensin converting enzyme inhibitors (ACEi), failure, chronic kidney disease and cognitive decline. angiotensin II receptor blockers (ARB), calcium chan- Most cases of hypertension have no known cause and nel blockers (CCB), beta blockers, alpha blockers and are termed essential hypertension. Secondary causes of diuretics. A number of national and international hypertension account for approximately 10% of cases, guidelines exist for the treatment of hypertension, and treatment of secondary hypertension generally with some differences between them. The seventh involves treating the underlying cause. Whatever the Joint National Committee on Prevention, Detection, aetiology, it is clear that controlling high arterial pres- sure improves prognosis and is an important compo- School of Medicine, King’s College London, London, UK nent of primary prevention of cardiovascular disease. Corresponding author: Persistent hypertension can lead to left ventricular Albert Ferro, British Heart Foundation Centre for Research Excellence, hypertrophy and remodelling of resistance arteries, Cardiovascular Division, King’s College London, 150 Stamford Street, both of which are associated with adverse cardiovascu- London SE1 9NH, UK. lar outcomes. Email: albert.ferro@kcl.ac.uk XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] 2 Journal of the Royal Society of Medicine Cardiovascular Disease 0(0) Evaluation and Treatment of High Blood Pressure cur- of a CCB and ACEi or ARB, with the further addition rently recommends thiazide diuretics should be used as of a diuretic if control is still not achieved. an initial therapy in most patients (although new guide- In approximately 10% of patients with hyperten- lines are due to be released soon); if the blood pressure sion, a combination of three antihypertensives (typic- remains uncontrolled (>160/100 mmHg), then a two- ally diuretic, CCB plus ACEi or ARB) is not effective at drug combination with a thiazide diuretic and either a controlling blood pressure. In these cases of ‘resistant CCB, ACEi or ARB is advocated. Guidance from the hypertension,’ the aldosterone antagonist spironolac- World Health Organisation dictates that the choice of tone is often added to the treatment regimen. antihypertensive should be based on cost effectiveness Aldosterone antagonism with spironolactone, or and any specific indications such as the particular bene- indeed with the newer drug eplerenone, has been fits of ACEi or ARBs in the context of renal disease. In shown to be effective at lowering blood pressure in England and Wales, the latest National Institute for such patients and has a range of beneficial cardiovas- 10–12 Health and Care Excellence (NICE) guidelines recom- cular effects, thus highlighting the potential bene- mend starting drug treatment in those with stage 1 fits of targeting aldosterone in the management of hypertension (>140/90 mmHg) with one or more add- resistant hypertension, especially where other cardio- itional risk factors (such as diabetes, end-organ damage vascular risk factors may coexist. and renal disease) and treating anyone with stage 2 hypertension (>160/100 mmHg); in Caucasian patients The importance of aldosterone within the under 55 years of age, an ACEi or ARB is advocated, renin angiotensin aldosterone pathway whilst in people of African/Caribbean origin and all those over 55, a CCB is recommended as these patients The renin angiotensin aldosterone system (RAAS; generally have lower plasma renin. If blood pressure is Figure 1) plays an essential role in blood pressure con- still not controlled, NICE recommends a combination trol through regulating fluid and electrolyte balance. Figure 1. The renin angiotensin aldosterone system. Also shown are the sites of action of ACEi, ARB, aldosterone synthase inhibitor and MR antagonist drugs. XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] Hargovan and Ferro 3 Angiotensin II is the main effector of the RAAS, acting In addition to its genomic effects, aldosterone is on the type I angiotensin II receptor resulting in thought to exert non-genomic actions, which are increased blood pressure by a combination of vasocon- mediated via effects on protein kinase C, intracellular striction, increased cardiac output, vascular remodel- calcium and cyclic adenosine monophosphate. It has ling and increased aldosterone secretion. been proposed that non-genomic effects could contrib- Angiotensin II increases the synthesis of aldosterone ute to vascular smooth muscle cell hypertrophy, vascu- by upregulating the CYP11B2 gene, which encodes the lar fibrosis and interstitial fibrosis of the kidney enzyme aldosterone synthase, in the zona glomerulosa alongside genomic effects of aldosterone, which also of the adrenal cortex. Aldosterone synthase expression mediate cardiovascular fibrosis. This provides a pos- 20,21 is also stimulated by potassium and adrenocortico- sible additional target for therapeutic intervention. 14,15 trophic hormone (ACTH). Aldosterone plays an important role in electrolyte Aldosterone antagonists homeostasis, through acting on mineralocorticoid receptors (MR) in the cortical collecting ducts of the Although prevention of angiotensin II generation or kidney to increase expression of sodium channels, lead- action would be expected to prevent the secretion of ing to sodium and water reabsorption which is coun- aldosterone, this is not universally the case. For exam- tered by potassium loss. The resultant increase in ple, the randomised evaluation of strategies for left ven- plasma volume leads to a rise in blood pressure. The tricular dysfunction (RESOLVD) trial showed that MR is a nuclear transcription factor that binds hor- suppression of the RAAS system with an ACEi and mone response elements and increases transcription of an ARB did not suppress aldosterone secretion in the 16 22 sodium channels. long term. This phenomenon has been described as The role of aldosterone in hypertension had first ‘aldosterone escape.’ In consequence of this, inhibiting been recognised in 1954 by Conn and Louis, when aldosterone exerts an additive effect to inhibiting angio- they cured a case of hypertension by removal of an tensin II as regards controlling blood pressure. It is adrenal adenoma which secreted excess aldosterone. believed that use of conventional agents that target The largest study to date has found that primary aldos- the RAAS leads to an upstream accumulation of teronism accounts for 11% of patients with hyperten- renin, which contributes to the rise in aldosterone sion, although this figure may vary according to levels both through overcoming RAAS inhibition by ethnicity and comorbidities. the law of mass action and by generating aldosterone Aldosterone also plays an important role in hyper- through alternative pathways that bypass the classical tension in the absence of primary aldosteronism. It has RAAS. been demonstrated that up to 15% of hypertensive Spironolactone was the first MR antagonist to be patients have an abnormally high aldosterone / renin developed, and is used for the treatment of hyperten- ratio; and in patients with resistant hypertension, this sion, primary hyperaldosteronism and peripheral proportion rises to around 25%. Thus, higher 24-hour oedema associated with cardiac failure and other urinary aldosterone levels have been found in patients pathologies associated with secondary aldosteronism. with resistant hypertension as compared to patients Unfortunately, spironolactone is not well tolerated, with controlled hypertension. mainly due to its lack of specificity for the MR: it The effects of aldosterone are more widespread than also binds to progesterone and androgen receptors, simply regulating sodium and potassium levels. leading to menstrual irregularities in women and Mineralocorticoid receptors are found in a large sexual dysfunction with painful gynaecomastia in range of tissues including adipose, cardiac myocytes, men. This adverse event profile prompted the search brain and vascular endothelium, cardiac fibroblasts for better tolerated MR antagonists. This led to the and vascular smooth muscle cells. Aldosterone acti- development of eplerenone, a compound that exhibits vation of mineralocorticoid receptors leads to upregu- reduced affinity for sex steroid receptors and so is less lation of NADPH oxidase and thereby increased prone to cause the sex hormone-related adverse effects production of reactive oxygen species (ROS). The gen- of spironolactone. However, as with spironolactone, eration of ROS leads to reduced bioavailability of nitric electrolyte imbalances in particular hyperkalemia can oxide, which is associated with impaired relaxation of occur in up to 5% of patients, especially in the pres- vascular smooth muscle cells, thereby leading to ence of renal dysfunction and in combination with increased peripheral vascular resistance and higher other potassium-retaining drugs such as ACEi or blood pressure. Furthermore, lower nitric oxide levels ARB. Eplerenone also exhibits reduced affinity for the are associated with endothelial dysfunction and MR compared to spironolactone. increased cell adhesion molecule expression, which Non-steroidal MR antagonists are currently being increase the risk of atherosclerosis. developed, and these may offer advantages over XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] 4 Journal of the Royal Society of Medicine Cardiovascular Disease 0(0) spironolactone and eplerenone. BAY94-8662 has been reduction in mortality. It is possible that the beneficial shown to be more selective for the mineralocorticoid effects of mineralocorticoid blockade seen in this study receptor than spironolactone and has greater affinity were due to changes in cardiac structure rather than than eplerenone. In a recent phase 2 study, BAY 94- blood pressure. From such evidence it can be inferred 8862 was shown to be safe and tolerable in patients that aldosterone is linked to organ damage, and that with chronic heart failure and mild chronic kidney dis- inhibiting its action provides added benefit over and ease. Furthermore, BAY 94-8862 was shown to be as above lowering of blood pressure. effective as spironolactone at reducing biomarkers of heart failure and CKD with a better adverse effect Aldosterone synthase inhibitors profile. Although spironolactone and eplerenone effectively lower blood pressure, they can cause reactive increases Aldosterone inhibition and end-organ in circulating renin and aldosterone levels, reducing the damage effectiveness of treatment. Furthermore, experimental As mentioned earlier, inhibition of aldosterone gives data suggest that some of the deleterious effects of rise to beneficial effects on end-organ function. This aldosterone may occur through non-genomic pathways, was indeed proved to be the case in the 4E (eplerenone, independently of stimulation of the MR. If non- enalapril, eplerenone and enalapril) trial, a double blind genomic pathways do contribute importantly to the randomised 9-month-long trial in patients with hyper- effects induced by aldosterone, drugs which inhibit tension and left ventricular hypertrophy. In this trial, aldosterone synthase would potentially offer an advan- eplerenone was equivalent to enalapril at reducing tage over MR antagonists in preventing activation of blood pressure, and the combination of enalapril and both genomic and non-genomic pathways. eplerenone caused a greater reduction in blood pressure Aldosterone production is largely controlled by than either monotherapy. Furthermore, left ventricular regulation of transcription of the CYP11B2 gene mass was reduced to the greatest extent by the combin- which encodes aldosterone synthase. This enzyme cata- ation therapy, followed by treatment with eplerenone lyses the final three rate-limiting steps of aldosterone alone. Treatment with enalapril alone caused the least synthesis (Figure 2). It is located in the mitochondria reduction in left ventricular mass. This study demon- and is part of the cytochrome P450 family. The syn- strated that eplerenone is highly effective at reducing thesis of aldosterone and cortisol are closely linked. target end-organ damage associated with hypertension, Cortisol production occurs in the zona fasiculata of and more complete blockade of the RAAS using an the adrenal cortex, the final step of cortisol synthesis ACEi and eplerenone combined provided the greatest involving the enzyme 11-b-hydroxylase which is degree of protection. It is important to note, however, encoded by the CYP11B1 gene. The CYP11B1 and that the short duration of this study means that the CYP11B2 gene are both located on the short arm extrapolation of long-term patient outcomes was not of chromosome 8. Transcription of the CYP11B1 gene possible. is stimulated by ACTH and that of the CYP11B2 gene Aldosterone is also linked to the pathogenesis of by angiotensin II and potassium. The similarity of renal damage. Observational studies have shown that aldosterone synthase and of 11-b-hydroxylase has ren- there is a correlation between aldosterone levels and dered it difficult to find a specific a specific inhibitor proteinuria in patients with diabetic nephropathy; and that selectively targets aldosterone synthase. clinical studies have shown improvements in protein- uria with eplerenone treatment. Preclinical studies of aldosterone synthase inhibition The role of aldosterone in heart failure is well estab- lished. The randomized aldactone evaluation study Fadrozole and its dextroenantiomer FAD 286, which (RALES) showed a 30% reduction in mortality in have inhibitory properties against aldosterone synthase, patients with severe heart failure when treated with have been experimentally tested preclinically but have 28 32–34 spironolactone in addition to usual therapy. The never been investigated in patients. In spontan- Eplerenone post acute MI heart efficacy and survival eously hypertensive rats, FAD286 dose dependently study (EPHESUS) trial showed that addition of epler- reduced urine and plasma aldosterone levels; however, enone to standard treatment reduced hospital readmis- in combination with spironolactone it caused severe sion by 23% in patients who had experienced an dehydration and hyperkalemia, thus highlighting the acute myocardial infarction complicated by left ven- potential danger of complete aldosterone inhibition tricular dysfunction. In this trial, eplerenone doses using combination therapies. of 25 mg daily, which had only a minor effect on In transgenic mice overexpressing human renin and blood pressure, were associated with a significant aldosterone, FAD286 reduced mortality, prevented XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] Hargovan and Ferro 5 Figure 2. Schematic of adrenal steroid biosynthesis. cardiac hypertrophy and matrix deposition in the heart aldosterone synthase, produce dose-dependent reduc- and kidney. However, it was not as effective as an ARB tions in aldosterone levels, reduce blood pressure and at reducing blood pressure. prevent end-organ damage. However, aldosterone syn- In rat models of congestive heart failure, FAD286 thase inhibition prevented end-organ damage to a simi- showed beneficial haemodynamic effects and improved lar extent as mineralocorticoid receptor antagonism, left ventricular function and remodelling to a similar suggesting that aldosterone does in fact mediate end- extent as spironolactone. organ damage via mineralocorticoid receptor depend- In spontaneously hypertensive rats, reduction in ent mechanisms. On the other hand, the discordant myocardial fibrosis by the two enantiomers of fadro- enantioselectivity of fadrozole on cardiac fibrosis, des- zole were compared to a mineralocorticoid recep- pite equal effects on circulating aldosterone levels, tor antagonist. At high doses, both the S and the argues for an effect of this drug which may be non- R enantiomers of fadrozole lowered plasma aldoster- aldosterone-mediated. Further studies are required to one levels to similar extents; but interestingly, only dissect out any possible effects of this drug which are R-fadrozole reduced cardiac fibrosis (by 50%) whereas not exerted through modulating aldosterone synthesis. S-fadrozole had no such effect. This raises the question The translational potential of FAD286 is also ham- of whether the antifibrotic effects of this drug are truly pered by the fact that it lacks selectivity for aldosterone mediated via reduction in plasma aldosterone or synthase, since it also inhibits 11-b-hydroxylase to a through other as yet unrecognised mechanisms. large extent; this leads to inhibition of cortisol synthesis In uninephrectomised rats on a high salt diet treated secondary to ACTH or stress. This lack of selectivity is with angiotensin II, both FAD286 and spironolactone likely to reduce the potential clinical usefulness of reduced blood pressure. After 8 weeks, FAD286 was FAD286. associated with a reduction in plasma aldosterone levels whereas spironolactone was associated with Clinical studies of aldosterone synthase inhibition increased plasma aldosterone. Nevertheless, both FAD286 and spironolactone reduced renal and cardiac The success of FAD286 in preclinical studies led to the hypertrophy and interstitial fibrosis to a similar development of LCI699, which has greater selectivity extent. for inhibition of CY11B2 over CY11B1, thereby In summary, preclinical studies of FAD286 have having less of an influence on cortisol. LC1699 is the generally been positive, although they have raised new first orally active aldosterone synthase inhibitor that questions. The drug has been shown to inhibit has been tested in humans. XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] 6 Journal of the Royal Society of Medicine Cardiovascular Disease 0(0) Phase 1 study. In a double blind, placebo controlled trial 1.0 mg daily had suppression of ACTH stimulated in 12 healthy normotensive subjects, LCI699 at doses of release of cortisol, indicating partial inhibition of 11- 0.5–3.0 mg once daily caused a dose-dependent b-hydroxylase (CYP11B1) although it did not reduce decrease in plasma and urine aldosterone levels. It did plasma cortisol concentrations and no patients devel- not affect cortisol levels at lower doses and was well oped signs of hypocortisolism. The most frequently tolerated. However, at 3 mg daily selectivity was lost occurring adverse effects were headache, dizziness and and it blunted cortisol responses to ACTH, and also nasopharyngitis, which were similar in the LCI699 and caused signs of hypoaldosteronism (postural tachycar- placebo groups. Hyperkalemia occurred in 3% of dia, mild hyponatraemia and reduced body weight). patients in both the LCI699 and placebo groups. The These results supported further evaluation of compound was safe and well tolerated. LC1699. A study by Andersen et al set out to find the max- imum tolerated dose of LCI699 with respect to corti- Phase 2 studies. In a single blind, proof of concept phase sol suppression by ACTH. In all, 63 patients were 2 a study, 14 hypertensive patients with primary aldos- randomised in a double-blind fashion to either pla- teronism received LCI699 0.5 mg daily for the first two cebo or various doses of LCI699. The trial found weeks followed by 1 mg daily for a further two weeks, dose-dependent reductions in both systolic and dia- and finally placebo for one further week. Plasma stolic blood pressures by LCI699. The maximum tol- aldosterone levels were reduced by up to 80% in a erated dose was found to be 1.3 mg once daily. dose-dependent manner with treatment, and this was LCI699 had no serious adverse effects and no patients accompanied by dose-dependent increases in deoxycor- developed signs or symptoms of adrenal ticosterone (the aldosterone precursor), confirming the insufficiency. inhibition of aldosterone synthase. The inhibitory In a study of 155 patients with treatment-resistant effects on aldosterone synthase were maintained hypertension, patients were randomised in a double throughout the study, with no escape phenomena and blind fashion to receive over 8 weeks either placebo, no rebound effect seen after treatment was with- eplerenone 50 mg twice daily or varying doses of drawn. Plasma potassium increased by a mean of LCI699 (0.25 mg twice daily, 0.5 mg once daily, 1 mg 0.73 mmol/L and there was a mild increase in plasma once daily or 1 mg twice daily). Eplerenone gave rise renin concentration. Although plasma cortisol levels to a significant reduction in systolic and diastolic were unaffected, there was evidence of inhibition of blood pressure (9.9 and 2.9 mmHg, respectively). 11-b-hydroxylase as both plasma ACTH and 11-dehy- Surprisingly there was no significant reduction in droxycortisol (the precursor to cortisol) were raised. either systolic or diastolic blood pressure with any Furthermore, all patients had a blunted cortisol dose of LCI699. However, LCI699 did suppress response to ACTH. The lack of selectivity for plasma aldosterone and increase deoxycorticosterone CYP11B1 and CYP11B2 is consistent with preclinical levels in a dose-dependent manner. The reasons for studies using fadrozole. Additionally, ambulatory sys- this discrepancy are not clear, and the findings are tolic blood pressures were modestly reduced by contradictory to those of the studies by Calhoun 4 mmHg over 4 weeks. It was concluded that up to et al. and Andersen et al. This merits further evalu- 1 mg daily of LC1699 was safe and well tolerated, and ation in larger trials and suggests that aldosterone syn- effectively reduced plasma aldosterone levels as well as thase inhibition may be of clinical use only in partially correcting hypokalaemia in patients with pri- combination with other antihypertensive agents; or mary hyperaldosteronism. at any rate may be more useful in reducing end- Calhoun et al. recently carried out a randomised organ damage by aldosterone rather than in lowering controlled, double blind phase 2 trial, in which 534 blood pressure. patients with mild to moderate primary hypertension The most recent trial compared aldosterone synthase received LCI699 0.25–1 mg daily, eplerenone 50 mg inhibition using LCI699 with mineralocorticoid recep- twice daily or placebo. After 8 weeks, there was a tor blockade in patients with primary hyperaldosteron- dose-dependent reduction of mean systolic blood pres- ism. In addition to usual medications, patients were sure with LCI699. The daily 1.0 mg dose significantly treated with LC1699 for 30 days followed by placebo reduced systolic blood pressure by a mean of washout for 1 week followed by another 30 days of 12.6 mmHg, while eplerenone 50 mg twice daily reduced treatment with eplerenone. Thirty days of treatment systolic blood pressure by a mean of 13.8 mmHg, com- with eplerenone reduced 24-hour ambulatory blood pared with placebo; 24-hour mean ambulatory diastolic pressure by 5 mmHg more than LCI699; however, and systolic blood pressure were reduced to similar LCI699 was associated with a 75% decrease in extents by eplerenone and LCI699 1.0 mg daily after 8 plasma aldosterone whilst eplerenone increased aldos- weeks. Twenty percent of patients receiving LCI699 terone levels by 89%. XML Template (2014) [4.2.2014–10:49am] [1–9] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/CVDJ/Vol00000/140001/APPFile/SG-CVDJ140001.3d (CVD) [PREPRINTER stage] Hargovan and Ferro 7 protection in hypertensive patient populations may Conclusions pave the way for a broader use of aldosterone blockers, The development of LCI699 has allowed assessment of and in the future possibly also of aldosterone synthase the benefits and safety of inhibiting aldosterone synthe- inhibitors, especially if more selective agents can be sis in hypertensive patients. Unfortunately, the lack of developed. selectivity of LCI699 at higher doses (above 3 mg daily) giving rise to inhibition of 11-b-hydroxylase Guarantor (CYP11B1) and alteration of the glucocorticoid axis Albert Ferro limits the dose that can be used. It is unlikely that LCI699 will supplant mineralocorticoid receptor block- Contributorship ers clinically as the latter are more effective at lowering Milan Hargovan performed the literature search. Milan blood pressure. The development in due course of a Hargovan and Albert Ferro wrote the paper second generation of more selective blockers of aldos- terone synthase should make it possible to test the value Funding of this approach, hopefully to achieve greater reduc- tions in blood pressure without affecting the gluco- This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. corticoid axis. It should be noted that inhibition of aldosterone synthesis is not free of risks. As with mineralocor- Conflict of interest ticoid receptor blockade, aldosterone synthase inhibi- None declared. tors are likely to cause hyperkalemia and hyponatraemia. Furthermore, their long-term effect References on kidney function is not known. 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Published: Feb 5, 2014

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