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B Lechner and others Medical treatment of PA 181:4 R147–R153 Review

THERAPY OF ENDOCRINE DISEASE Medical treatment of

Benjamin Lechner1, Katharina Lechner2, Daniel Heinrich1, Christian Adolf1, Finn Holler1, Holger Schneider1, Felix Beuschlein1,3 and Martin Reincke1 Correspondence 1Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilian University of Munich, should be addressed Munich, Germany, 2Department of Prevention, Rehabilitation and Sports Medicine, Technical University of Munich, to M Reincke Munich, Germany, and 3Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Email Zürich, Switzerland martin.reincke@med. uni-muenchen.de

Abstract

In patients with primary aldosteronism, specific treatment provides prognostic benefit over optimal antihypertensive therapy and is therefore crucial to reduce mortality and morbidity in this subgroup of patients with . Prognostic relevance has been shown for adrenalectomy in unilateral disease and for medical treatment with mineralocorticoid antagonists in bilateral adrenal hyperplasia. Collectively, evidence points to the superiority of surgical treatment compared to medical treatment. The causal approach of removing the mineralocorticoid excess, as well as the often-accompanying excess, might provide one biologically plausible explanation for the observation of slightly better outcomes with surgical therapy. However, in patients living with primary aldosteronism, medical treatment is often insufficient for three major reasons. First and foremost, no marker of sufficient blockade has yet been established and therefore adequate treatment of the aldosterone excess is often dismissed as a treatment goal. Second, side effects often limit patient compliance. Third, as recommendations differ from other indications like heart failure, dosing is often inadequate. The aim of this review is first to provide an overview over medical treatment options and second to review potential markers for treatment surveillance in patients with primary aldosteronism.

European Journal of European Journal of Endocrinology (2019) 181, R147–R153

Introduction refractory hypertension (1). Primary aldosteronism is characterized by inappropriately high plasma aldosterone Primary aldosteronism is the most common cause concentrations relative to suppressed plasma of surgically curable . The activity (2). A growing body of sound evidence suggests estimated prevalence is 4–6% in patients living with that the aldosterone excess poses a significantly increased hypertension in primary care, around 10% in specialized risk of cardiometabolic disease via activation of the hypertensive clinics, and reaches 20% in patients with

Invited Author’s profile Martin Heinrich Reincke is Professor of Endocrinology and Chair of Medical Department IV, Ludwig-Maximilians University in Munich. His research specialities include endocrine hypertension, mineralocorticoid and glucocorticoid action and research. Professor Reincke is heading a research team specifically exploring the prevalence and relevance of mineralocorticoid excess in resistant hypertension on the epidemiological, clinical, genetic and molecular levels. Prof. Reincke won the prestigious European Research Council Advanced Grant Award (2.5 Mio €) in 2016 and is the president-elect of the European Society of Endocrinology.

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-19-0215 European Journal of Endocrinology https://eje.bioscientifica.com in clinicalbloodpressureremission in17–62%and treated patients( and showed higher quality of life compared to medically MRA) antihypertensivemedication after6and12months adrenalectomyneededless(non- patients whounderwent surgically versusmedicallytreatedpatients.However, aldosteronism,bloodpressure wassimilarin primary vein sampling with CT scan to determine treatment in prospective SPARTACUS trial, which compared adrenal to medicaltreatmentwithspironolactone( in surgicallytreated PA patients compared showed greaterimprovementofhypertensionand treatment ( by adrenalectomybutnotafter1yearofspironolactone by Strauch adrenalectomized PA patients( higher riskofatrialfibrillationinmedicallytreatedversus 12 superiority ofsurgicaltreatmentinunilateraldisease( studiesspeaktothe evidence fromobservational with regardtocardiovascularoutcomes,linesofrecent adrenalectomy is superior to adequate medical treatment receptor antagonistsisthetherapyofchoice( disease, medicaltreatmentwithmineralocorticoid adrenalectomy is considered the gold standard, in bilateral ( distinguished becauseofdifferenttreatmentapproaches bilateral formsofthedisease.Theseconditionsmustbe aldosteronismisclassifiedintounilateraland Primary treatment options Types ofprimaryaldosteronismand aldosterone secretion. hypertension, whichislikelyduetomildinappropriate to counteracttheincreasedsaltretentioninresistant pressure ( to otherantihypertensivemedicationinloweringblood aldosteronism, and amiloride are superior resistant hypertension, despite the exclusionof primary therefore hasthepotentialtoimpactprognosis( aldosteronismand the riskassociatedwithprimary essential hypertension( aldosteronism comparedtomatchedpatientswith shown highermorbidityratesinpatientswithprimary thatseveralstudieshave plausibility fortheobservation mineralocorticoid receptor( 1 ). Whileinunilateraldisease,surgicaltreatmentvia Review , Although thereiscontroversyoverwhether Of note,recentdatasuggestthatinpatientswith Early specificmedicalorsurgicaltreatmentdecreases 13 , 14 11 , et al. 14 ). This has been explained by their potential 15 ). Moreover, inJapan anationwidesurvey , arterialstiffnesswasreducedsignificantly 16 18 ). Forexample,Rossi , 19 4 ). Ofnote,adrenalectomyresults , 5 , 1 6 , , 7 3 17 , ). Thisprovidesbiologic B Lechnerandothers 8 ) andinastudydone ). t al et 1 13 . showeda ). ). Inthe 9 , 10 ). 9 , of reninfromsuppressionbyexcessaldosteronehas are notsuppressed( after adrenalectomy if preoperative plasma renin levels aldosteronism haveahigherrateofpersistenthypertension glucose tolerance( ( co-secretion isassociatedwithBMI,insulinresistance than medicaltreatment( aldosterone excess,hasshownmorefavorableoutcomes adrenalectomy, whichremovestheglucocorticoidand that biologically plausibleexplanationfortheobservation aldosteronismandcouldprovidea mortality inprimary linked totheincreased cardiovascular morbidity and well asinbilateralhyperplasia( commoninaldosteroneproducingadenomasas very emerging evidencethatglucocorticoidco-secretionis ( biochemical remissionofaldosteroneexcessin93–100% essential hypertensiongroup). fairly even (45% female in the PA group, 51% in the hypertension) werequitehigh andthesexbalancewas (31.1 kg/m years intheessentialhypertension group)andBMIvalues at studyentry. Meanage(58 yearsinthePA group,57 the analysis.Thegroupswerematchedbydecadeofage were nottreatedwithMRantagonistsexcludedfrom adrenalectomy, hadapreviouscardiovascular eventor aldosteronism whounderwent as patientswithprimary ≥ ratio aldosteronism(definedasaldosterone-to-renin primary datawereinconsistentwith thediagnosisof laboratory over a25-yearperiod(1991–2016).Patientswhosebaseline and affiliatepartnerhospitalsincludedpatientsseen from theBrighamandWomen’s, theMassachusettsGeneral 41,853 essentialhypertensionpatients.Dataweresourced aldosteronism with medically treated patients with primary retrospective analysis the authorscompareddataof602 mineralocorticoid receptorantagonists( Hundemer depicted byimaging( BMI, targetorgandamageandsizeofthelargestnoduleas of hypertension,sex,antihypertensivemedicationdosage, clinical successafteradrenalectomyareknownduration to a wrong diagnosis of PA. Other factors that predict outcomes aftertreatment.Itcouldbe,however, alsodue intra-glomerular hemodynamicsleadingtolessfavorable been explainedbymoresevererenaldamageandaltered Medical treatmentofPA 20 1 1 , µg/L per h or negative confirmatory testing) as well testing) aswell µg/L perhornegativeconfirmatory ), leftventricular hypertrophy ( 15 Of note, surgical candidates with primary Of note,surgicalcandidateswithprimary Noteworthy, a recently publishedstudyby < ). Anotherlayerofcomplexityisaddedbythe 555 2 pmol/L per µg/L per h or plasma renin activity pmol/L perµg/Lhorplasmareninactivity inthePA group,29.8 t al. et sheds new light on the treatment with shedsnewlightonthetreatmentwith 22 23 ). 15 ). Thisclinicallyunfavorableescape ). Downloaded fromBioscientifica.com at09/30/202112:56:36PM 9 , 13 20 , kg/m , 14 181 21 21 ). Glucocorticoid 2 :4 ). Thishasbeen ) andimpaired in the essential intheessential 3 ). In this ). Inthis R148 via freeaccess European Journal of Endocrinology onists, themostcommonly usedagentsbeingspirono Treatment of choiceismineralocorticoidreceptor antag Medical treatmentoptions forPA limited. arevery different Advantages anddisadvantagesof cardiovascular long-termoutcome. essential hypertension,whichwouldexplainthebetter suppressed reninlevelscouldalso indicate the presence of adrenal veinsamplinginonly55%.Insuchascenario,non- testingwasonlyperformed in72%,and since confirmatory aldosteronism used in this study were rather loose ( imprecise ( aldosterone-to-renin ratioasascreeningtestisnotoriously aldosteronism.Itisworthmentioningthatthe of primary suppressed reninlevelscouldbesimplyasloppydiagnosis renin activitygroup( that non-compliancewasoverrepresentedinthesuppressed with spironolactone.Therefore,itmaybehypothesized renin activity, common,particularlyinmentreated isvery study. Second,non-compliance,whichleadstosuppressed a parameterwhichwasnotavailableintheaforementioned linked to morefavorablecardiovascularoutcomesinPA ( confounder, sodiumrestrictionhas been becausedietary with sodiumexcess,reninissuppressed.Thismaybea With sodiumrestriction, renintendstorise,whereas dietary ( should providecautionagainstoversimplifiedinference accompanying editorial,thereareseverallimitationsthat markerfortreatmentresponse. asasecondary serve might beapredictorofcardiovascularoutcomesandmay 24 mean bloodpressuredidnotdifferbetweenthegroups( risk profilealmostthreetimeshigher, despitethefactthat 134 patientswithsuppressedplasmareninactivityhada profile astheessentialhypertensiongroup,whereasthose renin activity ( outcomes: those67patientswithunsuppressedplasma between plasma renin activity and cardiovascular starting MRantagonists,therewasastrongcorrelation in whomplasmareninwasmeasuredatleast1monthafter aldosteronismpatients a subgroupanalysisof201primary 8.8 yearsforthosewithessentialhypertension.Ofnote,in group duringafollow-upof7yearsforpatientswithPA and aldosteronism compared to the essential hypertension of cardiovascular events in patientswithprimary 24 Review ). The authors thus concluded that plasmarenin activity ). First, plays a major role in renin regulation. ). First,sodiumplaysamajorroleinreninregulation. However, asJohnWFunderpointedoutinan The resultsshowanalmostdoubledincidence 26 ). The diagnostic criteria for primary ). Thediagnosticcriteriaforprimary ≥ 1 µg/L per h) showed an identical risk 24 ). Anotherreasonfornon- B Lechnerandothers 3 , 24 25 3 ), ), ), - - ,

day or even every other day administration has proven day or even every are longlasting(24–58 ( metabolization and high affinity to bind to plasma pharmacological properties( CYP11B2) intohydroxylationproductswithdifferent metabolization byadrenalenzymes(CYP11B1and spironolactone aswellcanrenoneundergofurther active metabolitecanrenone.Recentdatasuggestthat dethioacetylated toitsprincipalpharmacologically ( aldosteronism been approvedforthetherapyofprimary has beenclinicallyappliedsincetheearly1960s, spironolactone, anon-selectiveMRantagonistwhich effective ( amiloride ortriamterenearerecommended,whichless against MRAtherapy, -sparingdiureticslike lactone andeplerenone.Incaseofcontraindications viable option to consider in patients with antiandrogenic antiandrogenic effects( on themineralocorticoid receptor, with no adverse overspironolactone isitsrelativeselectiveness available andoff-labeluseis common.Theadvantageof However, its commonuseinheartfailuremakesiteasily it hastobeadministeredintermsofcompassionateuse. day), butnotinEuropeancountriesandAustraliawhere including PA in Japan and USA (maximal dose 100 spironolactone, is approvedfortreatment of hypertension at therightdose,hasbeenproventobeequallyefficacious as 34% ofpatientswereswitchedtoeplerenone. but in 57% of the spironolactone group. In consequence, libido werepresentin1%oftheadrenalectomygroup, menstrual disturbances,erectiledysfunctionanddecreased adverse eventsinbothsexes:,mastopathy, ahighrateofantiandrogenic the authorsobserved non-compliance( observed might beoneoftheexplanationsforcommonly gynecomastia and erectiledysfunction. Severe sideeffects which include painful and oversensitive nipples, painful of dose-dependentadverseeffects,especiallyinmen, affinity totheandrogenreceptor. Thiscausesavariety spironolactone isitsantiandrogenicactiondueto of spironolactonesignificantly(upto90%)( high-fat mealhasshowntoenhanceoralbioavailability biological effectsofspironolactone.Ingestionwitha C) andimpairedkidneyfunctionincreasehalf-life to beefficacious. Ofnote,severe hepaticcirrhosis (Child Medical treatmentofPA 28 ). Uponadministrationspironolactoneisrapidly In manycountriesincludingGermany, only The moreselectiveMR-antagonisteplerenone,which An importantdownsidetobeconsideredwith 1 > , 90%), thebiologicaleffectsofspironolactone 27 ). 30 h) ( Downloaded fromBioscientifica.com at09/30/202112:56:36PM ). Inthiscontext,eplerenone isa 29 30 ). Therefore,aone-timeper 28 ). IntheSPARTACUS trial https://eje.bioscientifica.com ). Duetotheextended 181 :4 29 ). R149 mg/ via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com *Status iscountry-dependent(onlyapproved forhypertensionincludingPAinUSAandJapan). Antiandrogenic sideeffects Maximal doseusedinstudies Maximal approveddose Starting dose Administration Contraindications Drug interactions Hepatic elimination Active metabolites Changes inbioavailabilitywithfoodintake Duration ofbiologicaleffect(h) Approved forPAtreatment Table 1 therapy regimeninPA, individualizedtreatmentiskey complications ofPA. Asthereisnota‘onesizefitsall’ Optimal medicaltherapyiscrucialtopreventthe PA patients Drug titrationinmedicallytreated in patientswithimpairedrenalfunction. However, potassiumlevelsneedtobecloselymonitored hepatic impairment,nodoseadjustmentisneeded( yet been investigated. In renal impairment and moderate this subgroupofpatients,itspharmacokineticshasnot with severehepaticimpairment(ChildC)becausein The use of eplerenone is contraindicated in patients does notaffectthebioavailabilityofeplerenone( ( aldosteronism inarandomizedhead-to-headcomparison shown tobeinferiorinloweringbloodpressureprimary at higherdosesthanspironolactone,sinceithasbeen agents. Inclinicalpractice,eplerenoneisadministered with otherpharmacologicalandnon-pharmacological eliminated byCYP3A4,andtherefore,pronetointeract daily administration( much shorterlasting(3–6 binding affinity( into activemetabolitesandhasalowerplasmaprotein- contrast tospironolactone,eplerenoneisnotconverted complications underspironolactonetreatment.In 32 Review ) ( Moreover, this pharmacologicalagent is hepatically Table 1 Comparison ofthepharmacologicalprofilesMRantagonists. ). Asopposedtospironolactone,foodintake 28 ). Therefore,itsbiologicaleffectsare 30 ). h) ( 31 B Lechnerandothers ). Thisrequiresatwice- 1 • • • None No Yes Yes (increasedabsorptionupto90%) 24–58 Yes Spironolactone Yes (painfulgynecomastia,painful and 400 mg/day 400 mg/day 25 mg –0 × loss oflibido,menstrualirregularities) oversensitive nipples,erectiledysfunction, /day Concomitant usewitheplerenone Addison’s disease 31 31 ). ). serum potassiumlevelsareofutmostimportance( of including pressuremonitoringandsurveillance superiority overoptimalbloodpressurecontrolinPA ( an importanttreatmentgoalandconveysprognostic by pharmacologicalMRreceptorblockadeconstitutes , causally targetingthealdosterone excess for optimalpatientbenefit.Inadditiontonormotensive spironolactone, using potassium as the read-out. Higher spironolactone, usingpotassiumastheread-out.Higher achieved inthemajorityofpatients( the beginning.Inourexperience,efficientMRblockadeis serum potassiumlevelsshouldbemonitoredfrequentlyin underlying favoringhypokalemia, hyperkalemia rarelylimitsuptitrationbecauseofthe after 4weekstoamendthespironolactonedose.Although uptitration accordingtobloodpressure( dose (e.g.25 MR antagonistsshould be administered at a low starting spironolactone, we often add amiloride to potentiate the spironolactone, weoftenaddamiloridetopotentiatethe males with insufficient treatment response under 50 guidelines recommendnottoexceed100 up to400 potassium levels.Whilesomestudiesinvestigateddoses plasma aldosteronelevelsandquitelowpre-treatment for optimaltreatment.Thosepatientshaveexcessive Nevertheless, insome rare cases, higherdosesarerequired gynecomastia, erectiledysfunctionandlossoflibido( because oftheantiandrogenicactionsleadingtopainful doses areusuallynotwelltolerated,particularlyinmales Medical treatmentofPA For optimaldiseasecontrol, regular follow-upvisits, In our outpatient clinic, we re-evaluate the patients In ouroutpatientclinic,were-evaluatethepatients mg/day of spironolactone, the Endocrine Society mg/day ofspironolactone,theEndocrineSociety mg spironolactoneperday)withaslow 2–3 • • • • • Yes (CYP3A4) No No 3–6 No* Eplerenone No 300 mg/day 100 mg/day 25 mg –0 inhibitors Combination withstrongCYP3A Hyperkalemia Severe hepaticcirrhosis(ChildC) induce orinhibitCYP3A4 Interacts withpharmaceuticalsthat Elevates levelsofDigoxin Downloaded fromBioscientifica.com at09/30/202112:56:36PM × /day 181 > 90%) with50 :4 1 ). mg/day ( Fig. 1 R150 1 ). In ). In 31 mg mg mg mg 1 via freeaccess ). ). ). ). European Journal of Endocrinology we switchtoathreetimesper dayregimen.Dosesupto twice daily. In those whodonotrespondadequately, achieve sufficientaldosterone blockadewith50 generally agooddosageto start.Mostofourpatients spironolactone fortherapeuticequivalence( In general,eplerenonemustbedosedtwiceashigh as three times per day administration should be considered. daily isnecessary. Incase of aninsufficientresponse,a aldosterone antagonismadministrationatleasttwice compared tospironolactone( consideration isthesignificantlyshorterhalf-life toswitchthemedicationeplerenone. try sufficient forsymptomcontrol.Inthelongrun,wealways foremost reducethedoseofspironolactone.Thisisoften clinic, in case of antiandrogenic side effects, we first and eplerenone must be considered ( of spironolactoneorswitchingthemedicationto often inducesbreastpainandmenstrualirregularities( tolerated inhigherdoses,butingestingabove100 blockade.Infemales,spironolactoneisusually ESC/ESH Guidelinesforthemanagementofarterialhypertension. MRA dosetitration.*Incaseofseverehyperkalemia( Figure 1 Review In ourexperience,25 If eplerenoneisusedforPA treatment,animportant In caseofantiandrogenicsideeffects,dosereduction mg eplerenonetwicedailyare B Lechnerandothers 31 1 ). Foranadequate ). In our outpatient 30 ). > 5.2 mmol/L) MRAreductionmustbeconsidered.**Accordingtothe 2018 mg/day mg/day 32 mg ).

potassium andsuppressed renin activitydespitehigh manuscript underreview). saltperceptionof ashiftinthesensory (Adolf diet oftenexceeding10 highsalt patients tendtospontaneouslyconsumeavery restriction ( sodium Another alternative,oradjunct,mightbedietary elevated serumpotassiumlevelsorhypotension). are nocontraindications(e.g.antiandrogensideeffects, MRA doseshouldbeconsidered,providedthatthere In case of persistent renin suppression, increasing the marker to evaluate successful aldosterone blockade ( antihypertensive drugsshouldbeconsidered( maximum toleratedMRAdose,addingfurther hyperkalemia. because ofreduceddrugclearanceandenhancedrisk carefully MRA titrationmustbemonitoredvery approved dosageis100 300 Medical treatmentofPA mg/day havebeenusedinstudies,butthemaximal In caseof poor bloodpressurecontrol, low serum Plasma reninactivitymightconstituteanadditional If bloodpressurecontrolissuboptimaldespite In patientswithseverehepaticorrenalimpairment, 24 ). In our experience, primary aldosteronism ). Inourexperience,primary mg/day ( Downloaded fromBioscientifica.com at09/30/202112:56:36PM g perday, potentiallybecause https://eje.bioscientifica.com 30 ). 181 :4 1 ). R151 t al et 3 via freeaccess ). ). ., ., European Journal of Endocrinology https://eje.bioscientifica.com The authors declare that there is no conflict of interest that could be could that interest of conflict perceived asprejudicingtheimpartiality ofthisreview. no is there that declare authors The Declaration ofinterest in thecontextofsaltconsumptionandcompliance. populations isneededtoconfirmtheseresults,especially conclusions from one single study. More data from larger contraindications. It isimportanttonotdrawprecipitous therapy shouldbeconsidered,providedtheabsence of suppressed plasmareninactivity, adjustment oftheMRA provide additionalinformation.Incaseofpersistently has beensuggestedasanadjunctmarkerthatmight optimal bloodpressurecontrol.Plasmareninactivity are potassiumlevelsintheuppernormalrangeand markersofadequatetreatment disease control.Primary improves adherence and under regular supervision antagonists isthegoldstandard.Slowdrugtitration as wellpotentiallyaccompanyinghypercortisolemia. adrenalectomy. Thiscausallyaddressesaldosteroneexcess, the standardofcareremainssurgicaltreatmentvia aldosteronism. In unilateral disease, relevance in primary Early diagnosis, and specific treatment, has prognostic Conclusion normalized reninlevelsissuperior. answer thequestionwhetheruptitrationofMRAtoward of patientstoevaluatecardiovascularendpointswill term randomizedstudiesinvolvingappropriatenumbers renin levelsonendothelialfunction.Finally, onlylong- be usedtodemonstratethesuperiorityof‘normalized’ In apilotstudy, flow-mediatedvasodilatationcould restoration ofnight-timedippingcouldbeemployed. relevant endpoint24-hbloodpressureprofileswith sensitive CRPasendpoints.Asanadditionalclinically parameters suchaspro-BNP, microalbuminuriaorhigh- managing PA treatment. Such a study could use surrogate whether uptitration using renin levels is superior in Future studiesshouldaddressbyaprospectivedesign of PA Future directionsinmedicaltreatment considered ( doses ofMRAmedication,non-compliancemustbe Review In bilateraldisease,medicaltreatmentwithMR 1 ). B Lechnerandothers

regarding theuseofeplerenoneinPAtreatment. Hide Naruse and Paolo Mulatero for sharing their experience and expertise The authors would like to thank Celso Gomez-Sanchez, Michael Stowasser, Acknowledgments of themanuscript. reviewed and edited the manuscript. All authors approved the final version authors other the and Reincke Martin manuscript. the drafted and search literature the did Lechner Benjamin review. the to contributed authors All Author contributionstatement ‘The 205/1 Deutsche CRC/Transregio Adrenal: CentralRelayinHealthandDisease’toAR,FBMR). the the by (within R), M (DFG) to Forschungsgemeinschaft (694913) No agreement (grant programme innovation and research 2020 Horizon Union’s European the under (ERC) (2013_A182 and 2015_A171 to M R), the European Research Council Registry Hyperaldosteronism Registry-Else-Kröner Conns German the of support in Stiftung Kröner-Fresenius Else the by supported was work This Funding References Medical treatmentofPA 8 7 6 5 4 3 2 1 Williams TA &Reincke M.MANAGEMENT ofENDOCRINEDISEASE: Monticone S, D'Ascenzo F, Moretti C,Williams TA, Veglio F, Gaita F Milliez P, Girerd X,Plouin PF, Blacher J,Safar ME&Mourad JJ. Catena C, Colussi G,Nadalini E,Chiuch A,Baroselli S,Lapenna R Mulatero P, Monticone S,Bertello C,Viola A, Tizzani D, Hundemer GL, Curhan GC,Yozamp N, Wang M &Vaidya A. Conn JW. aldosteronism: Plasmareninactivityinprimary Funder JW, Carey RM,Mantero F, Murad MH,Reincke M, Diagnosis and management of primary aldosteronism:theEndocrine Diagnosis andmanagementofprimary 8587(17)30319-4) Endocrinology a systematicreviewandmeta-analysis. aldosteronismcomparedwithessentialhypertension: primary & Mulatero P. Cardiovasculareventsandtargetorgandamagein jacc.2005.01.015) of Cardiology aldosteronism. with primary Evidence foranincreasedrateofcardiovasculareventsinpatients 80–85. aldosteronism aftertreatment. & Sechi LA.Cardiovascularoutcomesinpatientswithprimary 98 aldosteronism. term cardio-andcerebrovasculareventsinpatientswithprimary Iannaccone A, Crudo V, Burrello J,Milan A,Rabbia F 8587(17)30367-4) and Endocrinology aldosteronism:aretrospectivecohortstudy.primary Cardiometabolic outcomesandmortalityinmedicallytreated jama.1964.03070160046009) hypertension. importance indifferentialdiagnosisandresearch ofessential org/10.1210/jc.2015-4061) Endocrinology andMetabolism an EndocrineSocietyclinicalpracticeguideline. aldosteronism:casedetection,diagnosis,andtreatment: primary Shibata H, Stowasser M&Young JrWF. Themanagementof 4826–4833. (https://doi.org/10.1001/archinternmed.2007.33) 2005 2018 JAMA Journal ofClinicalEndocrinologyandMetabolism Journal (https://doi.org/10.1210/jc.2013-2805) 2018 45 6 1964 41–50. 1243–1248. 6 51–59. 190 Downloaded fromBioscientifica.com at09/30/202112:56:36PM (https://doi.org/10.1016/S2213- 2016 Journal oftheAmericanCollege Journal 222–225. Archives Medicine ofInternal (https://doi.org/10.1016/S2213- (https://doi.org/10.1016/j. 101 1889–1916. Lancet: Diabetesand (https://doi.org/10.1001/ 181 :4 Journal ofClinical Journal (https://doi. Lancet: Diabetes et al . Long- 2008 R152 2013 168 via freeaccess

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Accepted 11June2019 Revised versionreceived18June2019 Received 29March2019

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