{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:10:59Z","timestamp":1789135859258,"version":"build-2803163510"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Hum Hypertens"],"DOI":"10.1038\/s41371-026-01221-x","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:44:27Z","timestamp":1789134267000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Too much, too soon? The argument against initial combination therapy in stage I hypertension"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6559-023X","authenticated-orcid":false,"given":"Daniel J.","family":"McClintick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary C.","family":"Bowman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph E.","family":"Ebinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"1221_CR1","doi-asserted-by":"publisher","unstructured":"Stark BA, DeCleene NK, Desai EC, Hsu JM, Johnson CO, Lara-Castor L, et al. Global, regional, and national burden of cardiovascular diseases and risk factors in 204 countries and territories, 1990-2023. JACC. 2025;Focus Issue: Global Burden Of Disease Spotlight86(22):2167\u2013243. https:\/\/doi.org\/10.1016\/j.jacc.2025.08.015","DOI":"10.1016\/j.jacc.2025.08.015"},{"key":"1221_CR2","volume-title":"Global report on hypertension: the race against a silent killer","author":"World Health Organization","year":"2023","unstructured":"World Health Organization. Global report on hypertension: the race against a silent killer. Geneva: World Health Organization; 2023. ISBN 9789240075108"},{"key":"1221_CR3","doi-asserted-by":"publisher","first-page":"2338","DOI":"10.1016\/j.jacc.2025.12.091","volume":"87","author":"SS O\u2019Connell","year":"2026","unstructured":"O\u2019Connell SS, Whelton PK, Li F, Allouch F, Shapiro L, Vandenburg M, et al. Global hypertension 2000 to 2020. JACC. 2026;87:2338\u201351. https:\/\/doi.org\/10.1016\/j.jacc.2025.12.091","journal-title":"JACC"},{"key":"1221_CR4","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/S0140-6736(21)01922-X","volume":"398","author":"CK Chow","year":"2021","unstructured":"Chow CK, Atkins ER, Hillis GS, Nelson MR, Reid CM, Schlaich MP, et al. Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial. Lancet. 2021;398:1043\u201352. https:\/\/doi.org\/10.1016\/S0140-6736(21)01922-X. PubMed PMID: 34469767.","journal-title":"Lancet"},{"key":"1221_CR5","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1016\/S0140-6736(24)01744-6","volume":"404","author":"A Rodgers","year":"2024","unstructured":"Rodgers A, Salam A, Schutte AE, Cushman WC, de Silva HA, Di Tanna GL, et al. Efficacy and safety of a novel low-dose triple single-pill combination of telmisartan, amlodipine and indapamide, compared with dual combinations for treatment of hypertension: a randomised, double-blind, active-controlled, international clinical trial. Lancet. 2024;404:1536\u201346. https:\/\/doi.org\/10.1016\/S0140-6736(24)01744-6. PubMed PMID: 39426836.","journal-title":"Lancet"},{"key":"1221_CR6","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1001\/jama.2018.10359","volume":"320","author":"R Webster","year":"2018","unstructured":"Webster R, Salam A, de Silva HA, Selak V, Stepien S, Rajapakse S, et al. Fixed low-dose triple combination antihypertensive medication vs usual care for blood pressure control in patients with mild to moderate hypertension in Sri Lanka: a randomized clinical trial. JAMA. 2018;320:566\u201379. https:\/\/doi.org\/10.1001\/jama.2018.10359","journal-title":"JAMA"},{"key":"1221_CR7","doi-asserted-by":"publisher","first-page":"e006986","DOI":"10.1161\/JAHA.117.006986","volume":"6","author":"TM MacDonald","year":"2017","unstructured":"MacDonald TM, Williams B, Webb DJ, Morant S, Caulfield M, Cruickshank JK, et al. Combination therapy is superior to sequential monotherapy for the initial treatment of hypertension: a double\u2010blind randomized controlled trial. Journal of the American Heart Association. 2017;6:e006986 https:\/\/doi.org\/10.1161\/JAHA.117.006986","journal-title":"Journal of the American Heart Association"},{"key":"1221_CR8","doi-asserted-by":"publisher","first-page":"2393","DOI":"10.1016\/j.jacc.2024.08.025","volume":"84","author":"A Rodgers","year":"2024","unstructured":"Rodgers A, Salam A, Schutte AE, Cushman WC, de Silva HA, Di Tanna GL, et al. Efficacy and safety of a novel low-dose triple single-pill combination compared with placebo for initial treatment of hypertension. JACC. 2024;84:2393\u2013403. https:\/\/doi.org\/10.1016\/j.jacc.2024.08.025","journal-title":"JACC."},{"key":"1221_CR9","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1056\/NEJMoa1511939","volume":"373","author":"JT Wright Jr","year":"2015","unstructured":"SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103\u201316. https:\/\/doi.org\/10.1056\/NEJMoa1511939","journal-title":"N Engl J Med"},{"key":"1221_CR10","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1001\/jama.284.4.465","volume":"284","author":"JHM Perry","year":"2000","unstructured":"Perry JHM, Davis BR, Price TR, Applegate WB, Fields WS, Guralnik JM, et al. Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of strokethe systolic hypertension in the elderly program (SHEP). JAMA. 2000;284:465\u201371. https:\/\/doi.org\/10.1001\/jama.284.4.465","journal-title":"JAMA"},{"key":"1221_CR11","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1056\/NEJMoa0801369","volume":"358","author":"NS Beckett","year":"2008","unstructured":"Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. New England Journal of Medicine. 2008;358:1887\u201398. https:\/\/doi.org\/10.1056\/NEJMoa0801369","journal-title":"New England Journal of Medicine"},{"key":"1221_CR12","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1056\/NEJMoa2111437","volume":"385","author":"W Zhang","year":"2021","unstructured":"Zhang W, Zhang S, Deng Y, Wu S, Ren J, Sun G, et al. Trial of intensive blood-pressure control in older patients with hypertension. New England Journal of Medicine. 2021;385:1268\u201379. https:\/\/doi.org\/10.1056\/NEJMoa2111437","journal-title":"New England Journal of Medicine"},{"key":"1221_CR13","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1016\/S0140-6736(05)67185-1","volume":"366","author":"B Dahl\u00f6f","year":"2005","unstructured":"Dahl\u00f6f B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the anglo-scandinavian cardiac outcomes trial-blood pressure lowering arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895\u2013906. https:\/\/doi.org\/10.1016\/S0140-6736(05)67185-1. PubMed PMID: 16154016","journal-title":"Lancet"},{"key":"1221_CR14","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1001\/jama.2023.3322","volume":"329","author":"J Sundstr\u00f6m","year":"2023","unstructured":"Sundstr\u00f6m J, Lind L, Nowrouzi S, Hagstr\u00f6m E, Held C, Lytsy P, et al. Heterogeneity in blood pressure response to 4 antihypertensive drugs: a randomized clinical trial. JAMA. 2023;329:1160\u20139. https:\/\/doi.org\/10.1001\/jama.2023.3322","journal-title":"JAMA"},{"key":"1221_CR15","unstructured":"2017 ACC\/AHA\/AAPA\/ABC\/ACPM\/AGS\/APhA\/ASH\/ASPC\/NMA\/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines | Hypertension [Internet]. [cited 2026 Jun 2]. Available from: https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/HYP.0000000000000065?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed"},{"key":"1221_CR16","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1161\/HYPERTENSIONAHA.124.23508","volume":"82","author":"RB Barrett","year":"2025","unstructured":"Barrett RB, Riesser B, Martin B, Sachdev N, Rakotz MK, Sutherland SE, et al. Treatment in the first month after hypertension diagnosis improves blood pressure control. Hypertension. 2025;82:1129\u201336. https:\/\/doi.org\/10.1161\/HYPERTENSIONAHA.124.23508","journal-title":"Hypertension"},{"key":"1221_CR17","doi-asserted-by":"publisher","first-page":"2453","DOI":"10.1210\/clinem\/dgaf284","volume":"110","author":"GK Adler","year":"2025","unstructured":"Adler GK, Stowasser M, Correa RR, et al. Primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2025;110:2453\u201395. https:\/\/doi.org\/10.1210\/clinem\/dgaf284","journal-title":"J Clin Endocrinol Metab"},{"key":"1221_CR18","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1111\/j.1751-7176.2010.00397.x","volume":"13","author":"AH Gradman","year":"2010","unstructured":"Gradman AH, Basile JN, Carter BL, Bakris GL. Combination therapy in hypertension. J Clin Hypertens (Greenwich). 2010;13:146\u201354. https:\/\/doi.org\/10.1111\/j.1751-7176.2010.00397.x","journal-title":"J Clin Hypertens (Greenwich)"},{"key":"1221_CR19","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1161\/HYPERTENSIONAHA.112.201566","volume":"61","author":"AH Gradman","year":"2013","unstructured":"Gradman AH, Paris\u00e9 H, Lefebvre P, Falvey H, Lafeuille MH, Duh MS. Initial combination therapy reduces the risk of cardiovascular events in hypertensive patients: a matched cohort study. Hypertension. 2013;61:309\u201318. https:\/\/doi.org\/10.1161\/HYPERTENSIONAHA.112.201566. PubMed PMID: 23184383","journal-title":"Hypertension"},{"key":"1221_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejim.2024.05.033","volume":"126","author":"R Kreutz","year":"2024","unstructured":"Kreutz R, Brunstr\u00f6m M, Burnier M, Grassi G, Januszewicz A, Muiesan ML, et al. 2024 european society of hypertension clinical practice guidelines for the management of arterial hypertension. Eur J Intern Med. 2024;126:1\u201315. https:\/\/doi.org\/10.1016\/j.ejim.2024.05.033","journal-title":"Eur J Intern Med"},{"key":"1221_CR21","doi-asserted-by":"publisher","first-page":"e114","DOI":"10.1161\/CIR.0000000000001356","volume":"152","author":"DW Jones","year":"2025","unstructured":"Jones DW, Ferdinand KC, Taler SJ, Johnson HM, Shimbo D, et al. 2025 AHA\/ACC\/AANP\/AAPA\/ABC\/ACCP\/ACPM\/AGS\/AMA\/ASPC\/NMA\/PCNA\/SGIM guideline for the prevention, detection, evaluation and management of high blood pressure in adults: a report of the american college of cardiology\/american heart association joint committee on clinical practice guidelines. Circulation. 2025;152:e114\u2013218. https:\/\/doi.org\/10.1161\/CIR.0000000000001356","journal-title":"Circulation"},{"key":"1221_CR22","doi-asserted-by":"publisher","first-page":"e00258","DOI":"10.1161\/HYP.0000000000000258","volume":"83","author":"JB King","year":"2026","unstructured":"King JB, An J, Bellows BK, et al. Single-pill combination therapy for the management of hypertension: a scientific statement from the American heart association. Hypertension. 2026;83:e00258 https:\/\/doi.org\/10.1161\/HYP.0000000000000258","journal-title":"Hypertension"},{"key":"1221_CR23","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/jhh.2017.5","volume":"31","author":"R D\u00fcsing","year":"2017","unstructured":"D\u00fcsing R, Waeber B, Destro M, Santos Maia C, Brunel P. Triple-combination therapy in the treatment of hypertension: a review of the evidence. J Hum Hypertens. 2017;31:501\u201310. https:\/\/doi.org\/10.1038\/jhh.2017.5","journal-title":"J Hum Hypertens"},{"key":"1221_CR24","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1038\/s41371-023-00811-3","volume":"37","author":"AS Bryan","year":"2023","unstructured":"Bryan AS, Moran AE, Mobley CM, Derington CG, Rodgers A, Zhang Y, et al. Cost-effectiveness analysis of initial treatment with single-pill combination antihypertensive medications. J Hum Hypertens. 2023;37:985\u201392. https:\/\/doi.org\/10.1038\/s41371-023-00811-3","journal-title":"J Hum Hypertens"},{"key":"1221_CR25","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-024-19346-4","volume":"24","author":"G Morabito","year":"2024","unstructured":"Morabito G, Gregorio C, Ieva F, Barbati G, Mancia G, Corrao G, et al. Cost-effectiveness of single-pill and separate-pill administration of antihypertensive triple combination therapy: a population-based microsimulation study. BMC Public Health. 2024;24:1808 https:\/\/doi.org\/10.1186\/s12889-024-19346-4","journal-title":"BMC Public Health"},{"key":"1221_CR26","doi-asserted-by":"publisher","first-page":"e596","DOI":"10.1161\/CIR.0000000000000678","volume":"140","author":"DK Arnett","year":"2019","unstructured":"Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC\/AHA guideline on the primary prevention of cardiovascular disease: a report of the American college of cardiology\/American heart association task force on clinical practice guidelines. Circulation. 2019;140:e596\u2013646. https:\/\/doi.org\/10.1161\/CIR.0000000000000678","journal-title":"Circulation"},{"key":"1221_CR27","doi-asserted-by":"publisher","first-page":"e260937","DOI":"10.1001\/jamanetworkopen.2026.0937","volume":"9","author":"Z Qiu","year":"2026","unstructured":"Qiu Z, Liu G, Hu Y, Wang S, Liu B, Rimm EB, et al. Adherence to healthy lifestyle and risk of cardiometabolic diseases in individuals with hypertension. JAMA Netw Open. 2026;9:e260937 https:\/\/doi.org\/10.1001\/jamanetworkopen.2026.0937","journal-title":"JAMA Netw Open"},{"key":"1221_CR28","doi-asserted-by":"publisher","first-page":"i60","DOI":"10.1093\/eurheartjsupp\/suae019","volume":"26","author":"M Muselli","year":"2024","unstructured":"Muselli M, Bocale R, Necozione S, Desideri G. Is the response to antihypertensive drugs heterogeneous? Rationale for personalized approach. Eur Heart J Suppl. 2024;26:i60\u20133. https:\/\/doi.org\/10.1093\/eurheartjsupp\/suae019","journal-title":"Eur Heart J Suppl"}],"container-title":["Journal of Human Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41371-026-01221-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41371-026-01221-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41371-026-01221-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:44:29Z","timestamp":1789134269000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41371-026-01221-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":28,"alternative-id":["1221"],"URL":"https:\/\/doi.org\/10.1038\/s41371-026-01221-x","relation":{},"ISSN":["1476-5527"],"issn-type":[{"value":"1476-5527","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]},"assertion":[{"value":"12 June 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors report no relevant relationships with industry or other conflicts of interest with the material in this manuscript. The authors report no relevant disclosures to the writing of this paper. No external funding was used in the creation of the manuscript.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}