Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ynMcNally Ryan meta-analysis primary and in review potassium systematic and A aldosterone hypertension: plasma on diuretics of Effect hrfr,temi betv ftepeetsuywst efr ytmtcrve n eaaayi of meta-analysis and review systematic a by perform affected to was also as study is (such present (which diuretics the formation. [10–12] of aldosterone some debated on potassium objective and action main been RAAS; production inhibitory PA the the has direct Therefore, of have PA of regulation to activation increases known the of are also in antagonists) level diuretics role receptor the important whether mineralocorticoid from an but plays apart [8] treatment) fact, (PRA) diuretic In induce activity diuretics the conditions, renin . improving chronic thereby includes plasma [9] and resistance, which acute in peripheral Under [3] increase in action [4–7]. decline an hypertension of sustained of mechanism a defect as and complex haemodynamic volume more recognized underlying plasma have in is diuretics reduction the and which initial drugs, reducing an fibrosis, (PA) inhibitory by inflammation, RAAS aldosterone part to renal plasma in Compared and least and cardiovascular at II promoting working angiotensin factor hypertension [2]. risk remodelling of of cardiovascular treatment effects independent the the Block- an in blocking [1]. cornerstone actions salt or other a regulates several formation are amongst that proliferation RAAS system tissue of and neuroendocrine (BP) ers complex pressure blood a homeostasis, is water and (RAAS) with system related renin-angiotensin-aldosterone not is The PA in medication. hypertension, antihypertensive Change another in heterogeneity. with therapy untreated between-class diuretic INTRODUCTION previously no of subjects and RCTs in diuretic In BP of in In Conclusion: change classes the all potassium. 0.091. to with in = correlates PA change but P in potassium the 6.475, increase change with = an and relationship change Q is PA no 0.927 between 0.789), there relationship but loop (0.142, significant 0.440), BP a 0.466 (0.169, was systolic 0.304 there combination in antihypertensive, thiazide/thiazide-like and another CI); difference with 0.355) 95% untreated standardised (mean, of previously (0.174, average diuretic total subjects 0.264 The of A classes MRA/potassium-sparing criteria. relevancy all Results: inclusion/exclusion 1.49), for for pre-specified criteria. (0.37, similar abstract the was inclusion/exclusion The met change and pre-defined PA and 45 title a mean which EMBASE by to in of MEDLINE, according screened retrieved eligibility were firstly searched: for articles were were and perform assessed 1139 Titles PA databases we were on (CENTRAL). Three articles Here Trials therapy full-text Methods: humans. Controlled diuretic the before BP. and of of by and models effects Register regulated potassium animal the Central mostly in investigating in Cochrane is change trials factor level randomized-controlled important with (PA) of an correlation aldosterone meta-analysis be its plasma and to Despite blood shown review decrease systematic been kidneys. to a has the known potassium by are serum diuretics release activity, (RAAS), renin RAAS system stimulate renin-angiotensin-aldosterone and the (BP) of pressure drugs inhibitory to Different Aim: Abstract 2021 1, June Pharmacology Clinical of Department Sciences, and Medicine 3 2 1 igsCleeLno rts er onainCnr,Sho fCardiovascular of School Centre, Foundation Heart British London College King’s available not Affiliation London College King’s 1 uhaFarukh Bushra , 1 Chowienczyk J P , 1 2 n uaFaconti Luca and , 3 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. nossece n ieetduei oe 1]wt aclto ftesadrie endffrnei PA in difference mean standardised demographic change. the of the of of terms of calculation error in size with heterogeneity the standard and [15] between-study observations as no doses for of was obtained diuretic compensate number there were different p-value, to If and pressure the used placebo. inconsistencies from was blood estimated or model systolic was diuretic random-effects and it A either stated, potassium with change renin, treatment mean PA, after the in Englewood, baseline changes (Biostat, from 3 Net difference Version [14]. Software Meta-Analysis Jersey) Comprehensive used. to New using were accurate conducted units be was other to analysis Meta-analysis if judged analysis statistical was for and it pmol/L synthesis reports if to data graphical taken The converted Quantitative only was intervals. were Where graph aldosterone confidence recorded. the of from also from Units was or estimation 10%. measurement P-values an within in of available, errors, time treatment were standard the measurements placebo at deviations from of standard treatment during calculated If diuretic extracted. were and of the were available, these (SBP) duration before Where pressure reported treatment. (and blood not systolic before diuretic and and were potassium on during serum values renin, and between in difference difference before ( the mean and aldosterone and measurements, studies) therapy and placebo-controlled outcome background prevalence BP the of and For available) for presence (if values ethnicity available). (including distribution, (if protocol year sex author, diabetes age, used, average included: of dose size, This sample and controlled), form. diuretic(s) standard placebo a whether of using class (RJM) publication, author one of by independently extracted were Data abstracts articles. full-text and process the Titles collection reviewed disregarded. Data author The were same treatment. articles the background review and during stable and (RJM), were and to author only or Studies before one language therapy available by placebo. English previous screened results with the no were treatment with either to during PA to limited trials, added was examined was placebo-controlled search have therapy of to hypertension diuretic case arterial if required the pulmonary not eligible a were in had diuretics studies were or, subjects novel which investigating treatment All they in Studies diuretic studies if week. failure. were one as heart inclusion excluded least examining or were for at use old, of eligible clinical (MRA) duration years antagonist for were a receptor licensed [?]18 with mineralocorticoid Studies diuretic loop, subjects thiazide-like, potassium-sparing human thiazide, or abstract. a hypertensive either and in of effects performed title antihypertensive (RCT) by trial screened randomized-controlled initially were Papers material. criteria publications. supplementary relevant eligibility the for in and databases provided selection the is Study search MEDLINE to for used strategy Medical were search ‘diuretic’. terms full and non-MeSH blood The ‘potassium-sparing’, and and ‘thiazide-like’, (MeSH) potassium ‘thiazide’, serum headings included renin, subject used +/- keywords aldosterone The plasma affected pressure. they how examined which multi-therapy, Ci- 16 Non-Indexed to Other per- 16 (up & was to In-Process search (1946 Print, MEDLINE(R), 16 literature Ovid of to systematic and Ahead Daily A Epub MEDLINE(R) MEDLINE(R) Ovid [13]. Ovid Reporting tations, guidelines (Preferred databases; PRISMA Meta-Analyses) three with on and accordance formed Reviews in Systematic out carried for was Items meta-analysis and review systematic This PA. plasma in and PA. difference PA in the strategy in to increased Search difference relates sustained between BP a correlation in to decrease is the lead there METHODS if they if PA (b) if (a) classes of address establish diuretic measurements between to to and potassium were treatment hypertension outcomes treat diuretic to secondary after used The and were before diuretics available where were (RCT) trials clinical randomised th etme 00 n h ohaeCnrlRgse fCnrle ras(ETA)databases (CENTRAL) Trials Controlled of Register Central Cochrane The and 2020) September th etme 00.Suiswihwr nlddwr raso irtc sdete smn-or mono- as either used diuretics of trials were included were which Studies 2020). September 2 ± tnaddvainsadr ro)of error) deviation/standard standard th etme 00,EBS (1974 EMBASE 2020), September Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 6hddffrne nsrmptsimad2 a ieecsi R ohbfr n fe irtc All diuretic. background no after diuretics was and SBP, combination there where in before with studies differences In both diuretics, mmHg). had PRA loop -11.48] [-35.33, 26 in the (-23.4 studies, differences amount from largest included had apart the significantly, 45 23 by SBP pressure the and lowering Of potassium blood material. serum decreased supplementary in diuretics the differences P in had 49.4, found 26 mEq/L, = - 0.422) be (-0.983, (-0.327, (Q can 0.048 -0.617 heterogeneity combination SBP loop and between-class mEq/L, mEq/L significant 0.345) -0.78) (0.151, (-0.62, with 0.248 -0.275 sparing/MRA K+ thiazide/thiazide-like mEq/L, were: 0.251) potassium serum in plasma Changes previous potassium, pressure serum to blood on added diuretic and and was activity placebo diuretic renin of whom Effect (0.234, Meta-analysis: in diuretics, 0.392 Outcomes found. potassium-sparing those Secondary was was from for PA where classes MRA PA between studies separating in in homogeneity After In increase increase same 2C). 0.091. Figure the average similar, = 0.553, a the P (0.046, was 6.475, washout, 0.300 There antihypertensives: = use/a Q 2B). antihypertensive 0.789), Figure significant background (0.142, 0.550, difference a MRA/potassium- 0.466 no 1.49), standardised to combination was (0.37, average led and 0.927 The there classes 0.355) loop 2A). 0.440), PA diuretic (0.174, (Fig (0.169, mean all 0.264 0.304 heterogeneity therapy, in thiazide/thiazide-like sparing between-class difference was: diuretic no change Standardized With PA was 2D). mean 0.14). there in (Fig -0.36, but analysis PA CI present in (95% the increase -0.11 in aldosterone PA was on plasma placebo effect on after negligible diuretic a and had placebo most Placebo of the was Effect this Meta-analysis: as used Outcome studies. was ACE/ARB Primary (PRA) where the an activity patients in added, renin where renin was plasma studies of sub-analysis, diuretic those measure renin the For In common 50%. before 1. over medication table in antihypertensive in included was summarised another are acid with indapa- trials treated tielinic amiloride, individual previously eplerenone, hydrochlorothiazide, of loop spironolactone, were Details 62%), furosemide, torsemide. diuretics and canrenone, (28/45, Individual class. chlorthalidone, 7%). MRA/potassium-sparing MRA/potassium-sparing bendroflumethiazide, (3/45, (amiloride) 53%), the mide, combination diuretic was (24/45, and potassium-sparing class thiazide/thiazide-like 9%) a diuretic remaining were grouped for used (4/45, The were diuretic measurements commonly diuretics 1). most had of The potassium-sparing study (Figure Classes MRAs. one and reasons full-text remainder only MRA 198 various the as synthesis. remaining for with analysis qualitative The excluded the abstract. the were duplicates and for in of 153 title together included removal on and were After based eligibility total). articles excluded in for 45 were MED- (1139 assessed 769 initial 564 which The were Central 1). of articles (Figure and articles guidelines 384 967 PRISMA Embase per were results, as there chart 191 flow returned a in search detailed LINE is process selection study The studies of Description asymmetry RESULTS Egger’s and asymmetry plot funnel Begg’s of [17]. inspection tests by assessed was previously bias publication subjects between Potential in association the and establish data bias to overall potassium. Publication used the serum association was in in the method change SBP evaluate and same in change The to change aldosterone antihypertensive. moments and another of PA with method in untreated the difference using standardized performed between was meta-regression Random-effects [16]. test Q SBP Cochran’s and using Meta-regression potassium, assessed plasma was for heterogeneity calculated Statistical were PRA. differences < for mean differences Raw standardised (CI). interval and confidence 95% its and .5wscniee ttsial infiatadaltsswr 2-tailed. were tests all and significant statistically considered was 0.05 3 < .0,Fgr ) h nlsso R and PRA of analysis The 3). Figure 0.001, P Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. codn oteblneo h ciainbtentetotpso eetr hc oneatec other each counteract actions which complex receptors have of [24,25]. could types system two cardiovascular RAAS the the the ant on between of antithrombotic, activation actions activation biological elicits the their receptors of the AT2 in balance Thus, hand, the complex dysfunction, [23]. other to endothelial a receptor. effects the according hypertension, AT2 is On natriuretic promotes the damage. RAAS and water which and organ and the receptor inflammatory AT1 end production AT1 that the and aldosterone the here vasoconstriction, subtypes, beyond remodelling by as vascular stress are receptor mediated such topic to main largely II, this two are angiotensin important on of retention through however effects speculation acts is physiological and II classic It debate All angiotensin review. of which systematic subject in this is system harmful could of PRA be scope in occurred could the increase PA PRA differ that in increased suggesting raise the doesn’t RAAS. a review[22]) Whether which treatment, the systematic PA, after of published in activation untreated and previously by previously increase before a driven in measured an with SBP be also line to in was in change lead PRA finding with where diuretics (a associated studies that significantly the is is In which analysis but subjects. potassium diuretic, present serum of the of debate classes the change of of between of concomitant finding subject and/or activation still main diuretics suggesting is aldosterone. of The PA PRA of classes in regulator in specific increase important to increase an an relates by an this is accompanied if to debated which be unclear been leads also is [21]. has treatment would it diuretics populations PRA diuretic and of specific raised classes chronic in the various with that agent Wherever the combination on known RAAS. pharmacological of in action is therapy line of and first it diuretic mechanisms used monotherapy as effective,and long-term of considered as safe, been and effect are be short- have both agents the the can [18], Diuretics However, diuretic and review years that individuals. [19,20] systematically confirmed 50 hypertensive tolerated have to than well investigations in Several more study change agents. for first anti-hypertensive BP hypertension other the and of is potassium treatment this with slightlyin aware, was correlation are that its we size PA effect as 6). corrected far Figure a 0.14-0.29, As to CI missing leading (95% potentially (0.22 imputed fourteen estimate were correction, initial plot DISCUSSION fill’ the funnel and than the ‘trim less of significantly the not side using but left bias. bias = publication the (P publication potential regression on potential of linear studies suggestive for Egger’s and by size asymmetric suggested effect was also of size was effect bias vs. publication error of Presence standard of plot funnel The P -0.01, change –0.033, the CI bias between 95% Publication previously relationship –0.02, (coefficient were significant PA participants (coefficient the in a SBP with were changes was and studies associated of PA in there However, independent in was antihypertensive, 5A). were Figure another SBP SBP 0.49, in = with in P changes untreated/washout 0.009, change the –0.018, population, CI whether overall 95% –0.005, examine the SBP In in to PA. change in performed to change was diuretic meta-regression after aldosterone Random-effects Figure 4B). in 0.402, untreated/washout Figure change = previously 0.174, of P were = Relation 0.12, participants P -0.30, Meta-regression: the 0.06, were CI -0.31, studies 95% CI serum where -0.09, 95% with studies (coefficient -0.13, in associated relationship (coefficient was findings no PA similar was in with there change 4A) found whether we examine aldosterone to and in used potassium change also to was diuretic meta-regression after Random-effects potassium medication. serum antihypertensive trend in another change similar a of receiving with Relation those 0.846) Meta-regression: and (0.275, subjects 0.560 similar untreated was mmHg. and difference previously -10.75) PRA mmHg both (-18.78, mean in -8.40) -14.76 standardised antihypertensives: (-17.7, increase average previous -13.05 overall to was The added SBP was in diuretic whom decrease in average those the washout, use/a antihypertensive 4 < .0,Fgr 5B). Figure 0.001, < .0) fe adjustment After 0.001). Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. h uhr aen oflc fitrs odeclare. to sources interest Funding of conflict no of have version authors final The the results. approved the and interest interpret read authors of helping All Conflict BF manuscript. with the analysis of searches, majority data electronic the manuscript. performed the wrote the LF conducted PJC RJM & and research. RJM LF the RJM, extraction. designed and and selection concept study study the developed fall authors the All to related is which and contributions diuretics Author’s of classes between . differ subjects hypertension not untreated in does previously therapy which in diuretic PA SBP its that in in of demonstrates increase unrepresentative meta-analysis an dose and to review group high leads systematic at sparing this used MRA/potassium conclusion, was The In trials performed background hypertension). many were hypertension. a in studies primary in of to few in which used use relating very use spironolactone commonly size and current The of effect be not short ethnicity. the composed will relatively are of to mostly was groups estimate (which was studies according useful ethnic diuretics of a differ prevent duration loop specific PA others The with in in diuretic. on well- dose Studies of variable diuretics (since dose reported. a ethnicity standard of and not studies by effects was some results performed in if ethnicity were therapy stratify studies, studies determine to of many to majority unable in the required were because and We described) pre- Caucasians been limitations. above have in activity several rises RAAS to even an in difference after or subject established [32,33], normal is RAAS to [34,35]. review the mechanism returns of This escape often drugs so-called inhibitory level the other PA other for to to the levels compared similarly treatment PA aldosterone, that on of agents reported suppression/blockade these been initial of although has [31]. PA effects It populations similar regulating classes. specific showed in diuretic MRA in effect investigating relevant limited sub-analysis be that a the could suggest have Finally, secretion mechanism to might the seem the se that results potassium modify per suggestions Our dietary substantially potassium [11]. are high also of it there administration: concentration can reduces potassium intake serum hr acute potassium of 24 by low variation as aldosterone while induced plasma little responsiveness, glands in enhances as adrenal increase intake for the 25% intake a from produces aldosterone potassium For potassium of production. dietary of aldosterone mEq in stimulate 10 Changes can of potassium [10]. infusion in serum subjects, alterations in normal animals, increments other experimental in acute the in example, as RAAS, and well from man Apart as In PA. balance potassium. and is potassium potassium secretion serum aldosterone to in remodelling regulating change factor need cardiac between have major would correlation could facilitate any investigations identify turn could not dedicated in aldosterone did point, We which that PA this To suggested in that PA). elucidate conducted. raise been To and speculated in the has designed [28–30]. also rise limiting marker it be pressure be in inadequate useful since arterial could role is a se affecting it a there be hand per without play in might other effects could if change medication the pre-treatment beneficial dose the concomitant On to a diuretic analysis a warranted. opposed of increasing our are as use studies by In PA, the further detected example response. in hypothesis, be BP (for change can this to therapy change that confirm a relates diuretic suggests whether this PA guide on remains whether of to depending diuretic and use that of that treatment with for therapy class diuretic SBP suitable diuretic selecting to be [27]. from and would response review biomarker benefit dose-titration in systematic a will guiding published respect, recently who in that a patients In PRA by selecting in confirmed in not change was helpful of and is use speculative PRA potential that the evidence [26], is there Whilst 5 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 6 ign P,Toa ,Cade ,Cmso ,L ,Pg JW,eio.Ccrn adokfor Handbook Cochrane 2019. editor. Cochrane; WV, 2019). MJ July Page T, (updated Li 6.0 M, version 2000. Interventions research. Cumpston medical J, of in Chandler Reviews meta-analysis J, Systematic for Thomas Methods JPT, SF. TA Higgins Sheldon 16. DR, Jones KR, and Abrams Biostat, reviews AJ, 3. Sutton Version systematic 15. Meta-Analysis Comprehensive for H. items Rothstein 2013. & reporting J., NJ; Higgins, Preferred Englewood, L., Hedges, DG. M., 2009;62:1006–12. Borenstein, Altman Epidemiol. 14. Clin J, J Tetzlaff statement. 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Disclosures Trust. with Foundation partnership NHS in Centre Trust Hospital Foundation of Acknowledgements: Research College NHS Department King’s Biomedical Thomas’ and the comprehensive St London and (NIHR) from Guy’s College Research support to King’s Health awards financial Facilities for Research acknowledge Institute Clinical authors and National King’s The Foundation, the Heart Excellence. via British Research the Health from of studentship interdisciplinary Centre an by BHF supported is McNally Ryan Mr None 6 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. lotrn n lsioe ciao niio- nhmn.JCi nornlMtb 2002;87:448–52. Metab. 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Parati hypertension.1. and therapy C, review A diuretic Thomopoulos hypertension: 20. for thiazide Diuretics DA. of Sica GC, years Roush 19. Fifty PU. test. graphical Feig simple, a M, 2009;169:1851–6. by detected Moser meta-analysis in 18. Bias C. 1997;315:629–34. Minder J. M, Med Schneider GD, Br Smith M, Egger 17. 7 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. aua 04 10gPrle,4 52.8 54.2 54.3 45 Parallel, 48 Parallel, 48 Parallel, E100mg E50mg Placebo 2004* Saruta, 2004* Saruta, 2004 Saruta, ong 91HT 5gCosvr 168 51 Crossover, 25mg HCTZ 1991 Koenig, enegr 02E5m aall 9...7 gd enajse hne enajse hne .6... . . 4.26 ” ” ” ” ” ” ” ” changes Mean-adjusted ” ” ” ng/dL ” ” changes ” Mean-adjusted ng/dL ng/dL ng/dL ng/dL ng/dL ng/dL ng/dL 8 37.2 8 58 8 8 8 8 59.8 8 8 69 56.2 70 75 73 4 64 Parallel, . . 61 . 70 33 Parallel, . . . . . 33 . . . Parallel, ...... 49 . 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(A) previously in blood SBP (B) in and change the overall (A) 5: in Figure (mEq/L) difference. potassium standardised diff, serum Std in antihypertensive. change the antagonists. receptor and another mineralocorticoid with 4: MRA, treated interval; previously Figure confidence C) CI, antihypertensive, another placebo. with D) untreated and previously antihypertensive B) overall, A) vals. 3: mineralocorticoid MRA, Figure antihy- interval; another confidence CI, with difference; treated standardised previously antagonists. diff, Std receptor C) antihypertensive, placebo. D) another and with pertensive untreated previously B) overall, 2: Figure 1 Figure spironolactone 1984;48:1184–96. of Circulation. Effect KM. aldosteronism. Yagi primary S LEGENDS Hirano, in FIGURE Y steroids Kogure, adrenal M and Matsuo, volumes H Sakamaki, fluid T on Tajima, Y Ichikawa, S 35. RS iga.Fo-hr ficue xlddsuisaantapedfie erhcriteria. search pre-defined a against studies excluded & included of Flow-chart diagram. PRISM : eargeso lto h soito ewe encagsi Awt irtcteayand therapy diuretic with PA in changes mean between association the of plot Meta-regression unlpo ipaigpbiainba ntesuisrprigteipc fduei therapy diuretic of impact the reporting studies the in bias publication displaying plot Funnel oetposdslyn tnadzddffrnei enP n 5 ofiec nevl.A) intervals. confidence 95% and PA mean in difference standardized displaying plots Forest oetposdslyn a ieec nma lsaptsimad9%cndneinter- confidence 95% and potassium plasma mean in difference raw displaying plots Forest eargeso lto h soito ewe encagsi Awt irtctherapy diuretic with PA in changes mean between association the of plot Meta-regression 8 ± ± ± 01 4p/L70.4 pg/mL 24 & 12 20 8 ± ± ± ± ± ± ± ± ± ± ± ± 19 gm 7.46 ng/mL 3 93 11 . 02 gm 7(224.)4.4(s rm%cag)...... change) % from (est 46.14 (32.2-42.5) 37 pg/mL 24 40 9.1 00 968...%cag eotd%cag eotd...... reported change % reported change % reported change % reported change % reported change % reported change % ...... 8 8 8 69.6 63.3 68 10.02 11.3 10.55 . 768...%cag eotd%cag eotd...... ” reported change % ” reported change % ...... 8 8 66.7 57.6 9.33 7.7 . SM 068wesn/L6.98 ng/dL weeks 6-8 40 (SEM) 2.5 195 0po/ 7 2648 7 3049 3941 . (3.4-3.8) 3.6 (4.6-4.9) 4.8 (4.4-4.6) 4.5 (3.9-4.1) 4 (3.9-4.1) 4 (3.9-4.1) 4 (330-419) 374 (797-1129) 963 (893-1339) 1116 (276-438) 375 (276-438) 375 (276-438) 375 pmol/L pmol/L pmol/L 10 10 10 54 54 54 11.9 11.9 11.9 . 711 g 2.72 ng% 12 57.1 2.7 . 711 g 4.78 ng% 12 57.1 2.7 . 711 g 4.28 ng% 12 57.1 2.7 ± ± ± ± ± ± ± ± 0691.5 30.6 . 14.92 1.5 .55.15 1.25 .410.38 2.14 .8[E 8.11 [SE] 1.48 11.91 0.79 . 22.3 5.4 . 19.2 8.2 ± ± ± ± ± ± ± ± 2(m,78.9 (3m), 42 . 4.07 1.2 .14.12 1.31 264.1 12.6 4.2 9 .84.08 1.18 .4(1,11.47 (w1), 2.14 .34.5 2.93 ± 1(m 4.2 (6m) 31 ± .4(3 ...... (w3) 1.84 ...... 4.2 . 4.24 4.20 4.22 4.18 4.2 4.17 ...... ± ± ± ± ± ± ± . 4.5 0.4 . 4.5 0.2 . 4.3 0.3 . 4.4 0.4 .23.23 0.12 .23.68 0.12 .53.44 0.15 ± ± ± ± ± ± ± . 3) 4.3 (3m), 0.4 0.4 0.4 0.5 0.16 0.14 0.22 ± . (6m) 0.4 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ha 05ELR5m rsoe,2 71 20 Crossover, 50mg EPLER 2015 Ohta, orsej,21 CZ2m rsoe,2 0(56)7 gLPaeo 3(37)Mda Q 741(-.)3.82 (4-4.5) 4.1 87 IQR Median (33–74) 53 Placebo: ng/L 69 59.7 60.4 71 8 21 Parallel, 62 74 76 Parallel, 74 Parallel, 20 Crossover, 53.9 (55–63) 60 20 53.2 Parallel, 67 29 Parallel, Crossover, HCTZ 25mg 61 SPIRO Parallel, 1mg Placebo INDA 2010 12.5mg Kithas, HCTZ 2014 Vaclavik, 2014 Vaclavik, 2015* Ohta, 100-300mg 2019 E 25mg Solini, 75-225mg HCTZ SPIRO 2011* Parthasarathy, 2011 Parthasarathy, 2013 Dorresteijn, oase,22 PR+U+MLPrle,7 53.7 73 Parallel, SPIRO+FUR+AMIL 2020 Fouassier, ela,18 CZ5m rsoe,1 4(35)5. g10L10.99 ng/100mL 4 54.6 37 (23-58) 44 29 One-arm, 18 Crossover, 2.5mg INDA 50mg HCTZ 1985 Gerber, 1982 Belleau, eoa 06 A 0m aall 857.75 88 Parallel, 100mg CAN 2016* Derosa, eoa 06CN5m aall 757.15 87 Parallel, 50mg CAN 2016 Derosa, rm 02 PE 010g( R)Prle,45. 98n/L781. .1+0.20 4.31 12.4 7.8 ng/dL 8 49 54.2 Parallel,64 ARB) (+ 50-100mg EPLER 2002* Krum, rm 02 PE 010g( C)Prle,6 574 gd . 1843 +0.14 4.32 11.8 7.1 ng/dL 8 47 55.7 63 Parallel, ACE) (+ 50-100mg EPLER 2002* Krum, rm 02 lcb Addt R)Prle,5 514 gd . . .8+0.05 4.28 6.9 7.4 ng/dL 8 40 55.1 58 Parallel, ARB) to (Added Placebo 2002* Krum, rm 02Paeo(de oAE aall 05. 18n/L696743 +0.06 3.82 4.36 4.26 6.7 1257 416 6.9 pmol/L ng/dL 8 8 56.4 51 . . . 54.7 43 Crossover, 60 Parallel, ACE) to (added Placebo AMIL+HCTZ 2002 Krum, 1980 Henning, eoa 08 CZ1.-5gPrle,8 52.6 82 Parallel, 12.5-25mg HCTZ 2018* Derosa, err,18*PaeoPrle,1 49 53.4 49 16 Parallel, 81 Parallel, Parallel,16 50-100mg CAN Placebo 25mg CLTD 2018 Derosa, 1988* Ferrara, 1988 Ferrara, aahm,21*ELR2-0m aall 754.9 27 Parallel, 25-100mg EPLER 2016* Karashima, aahm,21 PR 2510gPrle,2 56.1 27 Parallel, 12.5-100mg SPIRO 2016 Karashima, aahm,21*E5m aall 366 23 Parallel, 50mg E 2016* Karashima, aahm,21 CZ62m aall 265 22 Parallel, 6.25mg HCTZ 2016 Karashima, ag 06SIO2-0gPrle,1 44.7 68 15 Parallel, 10 Parallel, 20-40mg SPIRO 12.5-25mg HCTZ 2016 Yang, 2015 Jarvis, ret 93 PR 0m rsoe,1 26 268n/ 7.8 ng/L 8 52.6 42-66 19 Crossover, 400mg SPIRO 1983* Kreeft, ret 93CT 0m rsoe,1 26 268n/ 7.8 ng/L 8 52.6 42-66 19 Crossover, 100mg CLTD 1983 Kreeft, wmnta,20 PR 55m rsoe,3 26...4po/ 150.84 pmol/L 4 . . . 62.6 33 Crossover, 25-50mg SPIRO 2008 Swaminathan, opas 97HT 0gO rsoe,950.5 9 Crossover, OD 50mg HCTZ 1987 Koopmans, i 04 lcb aall 654.9 36 Parallel, Placebo 2014* Ni, atee,21 ML5gB rsoe,2 0(57)6. mlL8 paeo 0 ...... 303 2) 299 (group 20.8 1), (Group 21.8 2) (Group 11.6 1), (Group 13.5 (placebo) (placebo) 84 84 ng/dL pmol/L pmol/L 2 66 4 4 55.7 60.9 60.9 51 (45-70) (45-70) 60 40 60 Parallel, 4 23 Crossover, 23 Crossover, Crossover, 25mg SPIRO BD 25mg SPIRO BD 5mg AMIL 50mg HCTZ 2014 Ni, 2012* Matthesen, 2012 Matthesen, 1982 Ferguson, ’onr 90HT rsoe,1 50.1 19 Crossover, HCTZ 1980 O’Connor, vnsn 93HT+MLPrle,1 854 2po/ 0 7. . .0(s rm%) from (est 3.80 3.3 478.4 after K+ 12.02 Serum 12.02 before 12.02 K+ 12.02 Serum pmol/L pmol/L 208 pmol/L pmol/L 5.7 pmol/L ng/100mL 4 4 36 4 4 24, 12, 4, 1, 43 43 43 43 12 100 43 50 after Aldosterone 26-58 50 50 50 53.9 49.3 48.5 55.3 14 Crossover, 52.6 13 Single-arm, 14 Crossover, before 14 14 Aldosterone Crossover, Crossover, 53 unit Aldosterone (weeks) measured 60 Time Parallel, 18 Parallel, (%) 15 Male 68 Parallel, Parallel, 47 Parallel, 16 Crossover, (years) Age BD 200mg 50mg SPIRO HCTZ size sample 100mg design, SPIRO Study 50mg SPIRO 25mg 1979 Spiro Brummelen, 1981* Ramsay 1981* Ramsay HCTZ+AMIL 25mg 1981* HCTZ Ramsay Placebo BD 1981 50mg Ramsay E 2007 Ubaid-Girioli, 2.5mg INDA 1983 Svendsen, E200mg 2011* Calhoun, dose 2011 Diuretic, Calhoun, 1982 Chalmers, 2004* Saruta, Year ID, Study 9 ± ± ± ± ± ± ± ± ± ± ± 04p/L1.44 pg/mL 4 70 8 06p/L327 222 pg/mL pg/mL 6 6 50 50 8 8 02 gd 5.4 ng/dL 24 50 6 04 g10L8(lcb)1. ID)44(lcb)36(INDA) 3.6 (placebo) 4.4 (INDA) 13.8 (placebo) 8 ng/100mL 8 44 10 ± ± ± ± ± ± ± ± ± ± ± ± ± ± 35 2n/L15.4 ng/dL 12 55 13 35 2n/L15.4 ng/dL 12 55 13 ± ± ± ± ± ± 242 gd 106 ng/dL 24 52.4 6 0 . gd 8.2 ng/dL 7.7 100 2 84 gm 85 pg/mL 48 68 2 84 gm 87 pg/mL 48 68 1 . 768n/ 7134.1 4.1 (w6) 3.95 (w4), 3.84 (w16) 3.95 (w4), 3.93 ...... 143 111 (16w) 33.3 (4w), 26.4 (16w) 44.1 (4w), 37.7 87 117 ng/L ng/L 18.6 20.1 ng/dL ng/dL 8 8 67.6 63.2 16 & 4 16 & 9.5 4 9.9 62.9 73.2 10.89 10.92 074. 8p/L140 pg/mL 48 48.1 10.7 . 074 gm 128 pg/mL 48 40.7 9.9 08...1 gd 18 ng/dL 12 . . . 10.8 . 564n/0m 8.5 ng/100mL 4 55.6 9.1 425. 2p/L23.4 pg/mL 12 58.3 14.2 236 2p/L23.8 pg/mL 12 60 12.3 . 678po/ 8. 7...... 172.3 379.8 reported change % 9.1 181.7 189.7 reported change % ng/dL pmol/L pmol/L . . . 12 8 46 8 66.7 8 59.7 7.2 8.7 72.9 9.1 10.76 .86. 2p/L68.77 pg/dL 12 63.6 9.18 .16. 2p/L58.64 pg/dL 12 65.5 8.91 037 2po/ 0 6-5)Mda+Q 7 1734 3.8 (177-344) 270 Median+IQR (69-152) 104 pmol/L 12 79 10.3 . 882 8p/L153.8 pg/dL 48 & 24 48.8 6.9 . 342 8p/L143.1 pg/dL 48 & 24 53.4 7.2 . 0 gm 48.3 pg/mL 4 100 2.6 ± ± ± ± ± ± ± ± ± ± ± ± ± ± 103 7 SM 83 (SEM) 6 . 8.2 5.4 ± ± ± ± ± . SM 13.8 (SEM) 0.8 . 11.8 4.7 . 14.4 4.8 . 11.56 4.8 . 11.8 4.8 . 14.1 2.2 . S]8.5 [SE] 0.9 ± ± 8 356 320 185 105 0184 60 5244 55 ± ± ± ± ± ± ± .51.01 0.95 0223.5 10.2 0924.5 10.9 S]98.4 [SE] 8 ± ± ± . 21.0 8.0 . 20.2 8.0 9157 49 . 10.90 5.6 31 68.50 63.19 46 77.76 54.67 .042.66 34.67 31.62 15.85 1.70 1.70 1.70 1.70 31(lcb)264.33 (placebo) 83.1 56164.1 25.6 25121.8 22.5 ± ± ± ± ± ± ± ± 4.1 5 ± ± ± ± ± ± ± ± ± ± ± ± . 4.3 3.3 . 1) 8.9 (1w), 0.6 6 ...... 166 227 83.9 88 43.9 84 *4.2 1* ± ± ± ± ± ± ± ± 184.3 11.8 . 4.3 4.57 9.3 0.43 . 4.2 1.2 05 ...... 10.5* 334.31 13.3 . 3.8 5.2 . 3.9 9.8 14.1 11 94.1 19 ...... 1.4 ± ± ± 3.8 9 .4...... 4.84 60 4.32 66.01 21 4.25 72.14 094.31 10.9 .83 3 3 3 1.78 1.32 1.41 2.45 0.14.4 107.81 79(m,169.4 (6m), 27.9 65(m,104.6 (6m), 16.5 ± . 4) 8.7 (4w), 0.5 ± ± 06(2)4.1 (12m) 30.6 32(2)3.9 (12m) 13.2 ± . 1w,6.7 (12w), 0.6 ± . 2w,6.8 (24w), 0.7 ± . 3w 4 (36w) 0.8 ± ± ± ± ± .43 0.04 .33.91 3.83 3.52 3.37 0.43 0.43 0.43 0.43 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± . +0.4 +0 0.5 0.5 . 4.3 0.4 . 3.6 0.1 . 4.2 0.3 . 4.3 0.3 . 4.3 0.1 . 4.1 0.1 . 4.3 0.3 . 4.8 0.3 .73.2 0.17 . 4.1 0.9 . 4.4 1.5 . 3.8 0.1 . 4.2 4.8 0.5 0.5 .54.47 0.35 .24.65 0.72 .34.50 0.43 . 5 0.4 . 3.35 0.4 . 3.8 0.4 . 3.8 0.5 . 4.1 0.4 ± ± 0.6 . 1) 3.1 (1W), 0.1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.5 0.1 0.3 0.3 0.1 0.1 0.2 0.37 0.26 1.4 0.7 0.1 0.31 0.40 0.45 0.3 0.35 0.43 0.48 0.44 ± ± ± ± 0.4 0.4 0.4 . 6) 3.5 (6m), 0.4 . 6) 4.3 (6m), 0.6 0.04 0.04 0.03 0.04 ± . 4) 3 (4W), 0.1 ± ± .*(12m) 0.3* . (12m) 0.7 ± . 1w,3.2 (12w), 0.1 ± . 2w,3.2 (24w), 0.1 ± . (36w) 0.1 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ee,18*CT 0m/a nnrsodr)Prle,954 9 Parallel, (non-responders) 100mg/day CLTD 1982* Meier, lhn 91FR 0gCosvr 251.6 45 12 Crossover, 11 Parallel, (responders) 100mg/day CLTD 40mg FURO 1982 Meier, 1981 Olshan, td D erDuei,ds td ein apesz g yas ae()Tm esrd(ek)Adseoeui lotrn eoeAdseoeatrSrmK eoeSrmK after K+ Serum before K+ Serum 212.7 pmol/L 24 . . . after Aldosterone . . . 70 before Aldosterone unit Aldosterone (weeks) measured Time (%) Male 17 24 Parallel, Parallel, than more = (years) * Age acid. phases. tienilic treatment = TIE or study. amiloride, size FURO arms = same sample chlortalidone, more AMIL the design, = Eplerenone, or in Study CLTD = result 1 canrenone, E one indapamide, = in = CAN placebo/diuretic INDA hydrochlorothiazide, a furosemide, = = with HCTZ treatment spironolactone, after = SPIRO and before measured was 1. TABLE 50mg CAN SPIRO dose Diuretic, 2002 Grandi, 2010* Kithas, Year ID, Study umr frnoie otoldathpresv rasi hc lsaadseoe(PA) aldosterone plasma which in trials antihypertensive controlled randomized of Summary 10 ± ± ± 06n/0m 4.1 ng/100mL 6 80 3 06n/0m 6.1 ng/100mL 6 80 5 ± 832 gd 107 ng/dL 24 58.3 5 . 0 gm lcb:66.1 Placebo: pg/mL 4 100 2.7 ± ± ± . Spn)9.1 (Supine) 0.9 . Spn)12.5 (Supine) 1.3 ± 1300 51 13234.6 31.3 ± Spn)85.4 (Supine) 9 ± ± ± ± . 22.8 & 3.4 ± 84...... 39 & 3.1 18.4 74.1 37 73 4.2 37.3* ± ± 524.0 15.2 . 3.8 5.9 ± ± ± ± . 3.4 0.1 . 4.3 0.1 . 3.1 0.1 . 4.2 0.2 ± ± ± ± 0.2 0.1 0.2 0.3 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary.

Included Eligibility Screening Identification 1. Figure

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throughCENTRAL Recordsidentified (n =564)(n splitSubjects by genetic profile(1) reported(2) Quantitativealdosterone changesnot Not all Subjects dividedby renin status (1) measured(1) Diureticbackground and no effect stated not (1) Quantitativeeffect on aldosterone anotherstudy (5) Duplicatepopulation alreadyin fromdiuretic beginning of trial(8) Diuretic in Urinary aldosterone(11) obtain accuracy(12) Graphical changestoodifficult to (8) Effectwith diureticadd Aldosteronenot measured(33) Full textnotavailable (3 Not subjects’all hypertensives (8) Abstract only(5) baselineOnly reported (18) Full

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Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. B C A Thiazide/Thiazide Drug class Drug class Q = 3.889, Q 3.889, = Combination Overall Combination Potassium Loop Potassium Loop Thiazide/Thiazide Overall Q = 5.977, Q 5.977, = Overall Combination Thiazide/Thiazide Drug class Potassium Loop Q 6.475, = D Placebo Drug class - - - sparing/MRA sparing/MRA sparing/MRA P P P = = 0.274 = = 0.113 = = 0.091 - - - like like like inmeans Stddiff - 0.111 inmeans inmeans inmeans Stddiff Stddiff Stddiff 0.360 0.466 0.264 0.927 0.304 0.300 0.405 0.234 1.128 0.132 0.392 0.542 0.294 0.682 0.436 - Lower Lower 0.360 limit 95% CI - - - Lower Lower Lower Lower 0.101 0.091 Lower 0.104 0.196 0.142 0.174 0.370 0.169 0.046 0.089 0.323 0.234 0.157 0.193 0.272 95% CI limit limit limit 95% CI 95% CI Upper 0.138 limit Upper Upper Upper 0.525 0.789 0.355 1.485 0.440 0.553 0.911 0.378 1.933 0.355 0.550 0.926 0.394 1.468 0.599 limit limit limit - 2.00 12 - - - 2.00 2.00 2.00 Stddiff in means and 95% CI - 1.00 Stddiff in means and 95% CI Stddiff in means and 95% CI Stddiff in means and 95% CI - - - 1.00 1.00 1.00 0.00 0.00 0.00 0.00 1.00 1.00 1.00 1.00 2.00 2.00 2.00 2.00 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. Thiazide/Thiazide Combination Placebo Drug class Potassium Overall Loop Drug class Q = 49.39, Q 49.39, = Drug class Overall A D C Q = 27.70, Q 27.70, = Overall Combination Potassium Thiazide/Thiazide Combination Thiazide/Thiazide Drug class Potassium Q = 24.96, Q 24.96, = Loop B - sparing/MRA - - sparing/MRA P sparing/MRA P P < < 0.0001 < < 0.0001 < < 0.0001 - like - - like like Difference Difference inmeans Difference Difference Difference Difference inmeans 0.009 Difference Difference inmeans inmeans ------0.135 0.617 0.275 0.048 0.248 0.280 0.440 0.618 0.413 0.229 - 0.081 0.170 0.500 0.207 - Lower Lower 0.032 limit - - - - 95% CI Lower Lower - - - - 0.524 0.327 0.983 0.415 0.151 Lower Lower 0.759 1.111 1.080 0.655 0.049 - - limit Lower Lower 0.092 0.176 95% CI limit 0.172 0.133 95% CI limit 95% CI Upper 0.050 limit - - - - 0.251 0.135 Upper 0.254 0.422 0.345 0.157 0.171 Upper 0.199 0.231 0.409 limit Upper limit 0.433 0.828 0.281 0.013 13 limit - 1.00 - - 1.00 1.50 - 1.00 Difference Difference in means and95% CI - Difference Difference in means and95% CI 0.50 Difference Difference in means and95% CI Difference Difference in means and95% CI - - 0.50 0.75 - 0.50 0.00 0.00 0.00 0.00 0.50 0.50 0.75 0.50 1.00 1.00 1.50 1.00 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary.

Standardized mean difference in PA (pmol/L) Standardized mean difference in PA (pmol/L) - - - - 1.50 1.00 0.50 0.00 0.50 1.00 1.50 2.00 2.50 0.20 0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 - - 1.3 1.3 A B - - 1.0 1.0 - - 0.8 0.8 - - 0.5 0.5 - - 0.3 0.3 Δ 14 Δ Potassium ( Potassium Potassium ( Potassium 0.0 0.0 mEq mEq 0.3 0.3 /L) /L) 0.5 0.5 0.8 0.8 1.0 1.0 1.3 1.3 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary.

Standardized mean difference in PA (pmol/L) Standardized mean difference in PA (pmol/L) ------0.75 0.50 0.25 1.50 1.00 0.50 0.00 0.50 1.00 1.50 2.00 2.50 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 - - 40.0 40.0 A B - 35.0 - 35.0 - 30.0 - 30.0 - 25.0 - 25.0 - 20.0 15 Δ Δ SBP (mmHg)SBP SBP (mmHg)SBP - - 20.0 15.0 - 10.0 - 15.0 - 5.0 - 10.0 0.0 - 5.0 5.0 10.0 0.0 Posted on Authorea 1 Jun 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162257796.64065063/v1 — This a preprint and has not been peer reviewed. Data may be preliminary.

Standard Error 0.8 0.6 0.4 0.2 0.0 - 2.0 - 1.5 - 1.0 - 0.5 Std diff Std diff in mean PA 16 0.0 0.5 1.0 1.5 2.0