{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:25:51Z","timestamp":1793831151853,"version":"4.6.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T00:00:00Z","timestamp":1759708800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":31,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sodium\u2013glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist (nsMRA) finerenone have each been shown to individually improve heart failure events among patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF\/HFpEF). Moreover, the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril\/valsartan has been shown to improve outcomes in patients with HFmrEF\/HFpEF with a left ventricular ejection fraction (LVEF) below normal (&lt;60%). However, the expected benefits of the combined use of these agents with long-term administration are not well defined. Here, in this cross-trial analysis of DELIVER, FINEARTS-HF and PARAGON-HF, combined use of SGLT2i and nsMRA therapies was estimated to reduce the risk of cardiovascular death or first worsening heart failure event by 31% in the overall population (hazard ratio 0.69; 95% confidence interval 0.59\u20130.81), while combined use of SGLT2i, nsMRA and ARNI therapies was estimated to reduce risk by 39% in patients with HFmrEF\/HFpEF and an LVEF &lt;60% (hazard ratio 0.61; 95% confidence interval 0.48\u20130.77). With long-term use, combined SGLT2i and nsMRA therapies in a 65-year-old patient with HFmrEF\/HFpEF, or combined SGLT2i, nsMRA and ARNI therapies in a 65-year-old patient with an LVEF &lt;60%, were projected to afford 3.6 (2.0\u20135.2) or 4.9 (2.5\u20137.3) additional years free from cardiovascular death or a heart failure event, respectively. Combined therapy was estimated to result in meaningful gains in event-free survival across a broad age range, from 55 to 85\u2009years. Among patients with HFmrEF and HFpEF, the potential aggregated long-term treatment effects of early combination medical therapy with SGLT2i and nsMRA (and ARNI in selected individuals) are projected to be substantial.<\/jats:p>","DOI":"10.1038\/s41591-025-04037-3","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T08:54:10Z","timestamp":1759740850000},"page":"325-331","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Lifetime benefits of comprehensive medical therapy in heart failure with mildly reduced or preserved ejection fraction"],"prefix":"10.1038","volume":"32","author":[{"given":"Muthiah","family":"Vaduganathan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Claggett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safia","family":"Chatur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1443-0701","authenticated-orcid":false,"given":"Akshay S.","family":"Desai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4306-5317","authenticated-orcid":false,"given":"Pardeep S.","family":"Jhund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6387-1351","authenticated-orcid":false,"given":"Orly","family":"Vardeny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6514-0723","authenticated-orcid":false,"given":"Bela","family":"Merkely","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8780-720X","authenticated-orcid":false,"given":"Josep","family":"Comin-Colet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose F.","family":"Kerr Saraiva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5655-8201","authenticated-orcid":false,"given":"Sanjiv J.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1903-0018","authenticated-orcid":false,"given":"Carolyn S. P.","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7456-1570","authenticated-orcid":false,"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5446-9969","authenticated-orcid":false,"given":"Kieran F.","family":"Docherty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6317-3975","authenticated-orcid":false,"given":"John J. V.","family":"McMurray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3698-9597","authenticated-orcid":false,"given":"Scott D.","family":"Solomon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"4037_CR1","doi-asserted-by":"publisher","first-page":"2476","DOI":"10.1016\/j.jacc.2017.08.074","volume":"70","author":"KS Shah","year":"2017","unstructured":"Shah, K. S. et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J. Am. Coll. Cardiol. 70, 2476\u20132486 (2017).","journal-title":"J. Am. Coll. Cardiol."},{"key":"4037_CR2","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","volume":"385","author":"SD Anker","year":"2021","unstructured":"Anker, S. D. et al. Empagliflozin in heart failure with a preserved ejection fraction. N. Engl. J. Med. 385, 1451\u20131461 (2021).","journal-title":"N. Engl. J. Med."},{"key":"4037_CR3","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1056\/NEJMoa2206286","volume":"387","author":"SD Solomon","year":"2022","unstructured":"Solomon, S. D. et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N. Engl. J. Med. 387, 1089\u20131098 (2022).","journal-title":"N. Engl. J. Med."},{"key":"4037_CR4","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1056\/NEJMoa2407107","volume":"391","author":"SD Solomon","year":"2024","unstructured":"Solomon, S. D. et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N. Engl. J. Med. 391, 1475\u20131485 (2024).","journal-title":"N. Engl. J. 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Lancet 403, 1083\u20131092 (2024).","journal-title":"Lancet"},{"key":"4037_CR12","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.1161\/CIRCULATIONAHA.121.058929","volume":"145","author":"M Vaduganathan","year":"2022","unstructured":"Vaduganathan, M. et al. Estimating the benefits of combination medical therapy in heart failure with mildly reduced and preserved ejection fraction. Circulation 145, 1741\u20131743 (2022).","journal-title":"Circulation"},{"key":"4037_CR13","doi-asserted-by":"publisher","first-page":"2307","DOI":"10.1002\/ejhf.2722","volume":"24","author":"M Yang","year":"2022","unstructured":"Yang, M. et al. Dapagliflozin in patients with heart failure with mildly reduced and preserved ejection fraction treated with a mineralocorticoid receptor antagonist or sacubitril\/valsartan. Eur. J. Heart Fail. 24, 2307\u20132319 (2022).","journal-title":"Eur. J. 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Sodium\u2013glucose cotransporter 2 inhibitor with and without an aldosterone antagonist for heart failure with preserved ejection fraction: the SOGALDI-PEF trial. J. Am. Coll. Cardiol. 86, 320\u2013333 (2025).","journal-title":"J. Am. Coll. Cardiol."},{"key":"4037_CR17","doi-asserted-by":"publisher","unstructured":"Agarwal, R. et al. Finerenone with empagliflozin in chronic kidney disease and type 2 diabetes. N. Engl. J. Med. https:\/\/doi.org\/10.1056\/NEJMoa2410659 (2025).","DOI":"10.1056\/NEJMoa2410659"},{"key":"4037_CR18","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.1056\/NEJMc1509753","volume":"373","author":"B Claggett","year":"2015","unstructured":"Claggett, B. et al. Estimating the long-term treatment benefits of sacubitril\u2013valsartan. N. Engl. J. Med. 373, 2289\u20132290 (2015).","journal-title":"N. Engl. J. 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Blinded withdrawal of long-term randomized treatment with empagliflozin or placebo in patients with heart failure. Circulation 148, 1011\u20131022 (2023).","journal-title":"Circulation"},{"key":"4037_CR22","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1161\/CIRCULATIONAHA.121.057736","volume":"145","author":"BL Neuen","year":"2022","unstructured":"Neuen, B. L. et al. Sodium\u2013glucose cotransporter 2 inhibitors and risk of hyperkalemia in people with type 2 diabetes: a meta-analysis of individual participant data from randomized, controlled trials. Circulation 145, 1460\u20131470 (2022).","journal-title":"Circulation"},{"key":"4037_CR23","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1001\/jamacardio.2016.4733","volume":"2","author":"AS Desai","year":"2017","unstructured":"Desai, A. S. et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril\/valsartan compared with enalapril: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol. 2, 79\u201385 (2017).","journal-title":"JAMA Cardiol."},{"key":"4037_CR24","doi-asserted-by":"publisher","first-page":"1938","DOI":"10.1016\/S0140-6736(22)02076-1","volume":"400","author":"A Mebazaa","year":"2022","unstructured":"Mebazaa, A. et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial. Lancet 400, 1938\u20131952 (2022).","journal-title":"Lancet"},{"key":"4037_CR25","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1056\/NEJMoa2410027","volume":"392","author":"M Packer","year":"2025","unstructured":"Packer, M. et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N. Engl. J. 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S. et al. Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis. Lancet 404, 1119\u20131131 (2024).","journal-title":"Lancet"},{"key":"4037_CR34","doi-asserted-by":"publisher","first-page":"e012437","DOI":"10.1161\/CIRCHEARTFAILURE.124.012437","volume":"17","author":"M Chimura","year":"2024","unstructured":"Chimura, M. et al. Finerenone improves outcomes in patients with heart failure with mildly reduced or preserved ejection fraction irrespective of age: a prespecified analysis of FINEARTS-HF. Circ. Heart Fail. 17, e012437 (2024).","journal-title":"Circ. Heart Fail."},{"key":"4037_CR35","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1002\/ejhf.3535","volume":"27","author":"X Wang","year":"2025","unstructured":"Wang, X. et al. Effect of sacubitril\/valsartan in heart failure with preserved ejection fraction across the age spectrum in PARAGON-HF. Eur. J. Heart Fail. 27, 96\u2013106 (2025).","journal-title":"Eur. J. Heart Fail."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04037-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04037-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04037-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T15:02:39Z","timestamp":1769007759000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-04037-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,6]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["4037"],"URL":"https:\/\/doi.org\/10.1038\/s41591-025-04037-3","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,6]]},"assertion":[{"value":"17 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"M.V. has received research grant support, served on advisory boards or had speaker engagements with Alnylam Pharmaceuticals, American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Esperion, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Recordati, Relypsa, Roche Diagnostics, Sanofi and Tricog Health, and participates on clinical trial committees for studies sponsored by Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Galmed, Impulse Dynamics, Novartis, Occlutech and Pharmacosmos. B.L.C. has received personal consulting fees from Alnylam, Bristol Myers Squibb, Cardior, Cardurion, Corvia, CVRx, Eli Lilly, Intellia and Rocket and has served on a DSMB for Novo Nordisk. S.C. is supported by the Canadian Child\u2019s Scholarship from the Libin Institute of Alberta\/Cumming School of Medicine. A.S.D. has received institutional research grants (to Brigham and Women\u2019s Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis and Pfizer as well as personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily and Zydus. P.S.J. reports speakers\u2019 fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications and Sun Pharmaceuticals; advisory board fees from AstraZeneca,Boehringer Ingelheim and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc and Roche Diagnostics. P.S.J.\u2019s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis and Novo Nordisk. P.S.J. is also Director of GCTP Ltd. O.V. has received grants from AstraZeneca and Cardior, and institutional research support from Bayer and Cardurion. B.M. has received advisory board fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, Duke Clinical Institute, Medtronic and Novartis. B.M.\u2019s institution has received fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, Duke Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo and Vifor Pharma. F.M. has received consultation fees and research grants from AstraZeneca, Baliarda, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Gador, Milestone, Novartis, Pfizer and St Lukes University. J.C.-C. has received grants from Novartis, Vifor Pharma, AstraZeneca and Orion Pharma and has received personal fees from Bayer, Boehringer Ingelheim, Vifor Pharma, Novartis, AstraZeneca and Orion Pharma. J.F.K.S. has served on advisory boards for and received consulting fees and honoraria from Bayer, Boehringer Ingelheim, Eli Lilly, Hypera, Medtronic, Merck Sharp & Dohme, Novartis, Novo Nordisk and Viatris. S.J.S. has received research grants from NIH (U54 HL160273, X01 HL169712, R01 HL140731 and R01 HL149423), AHA (24SFRNPCN1291224), AstraZeneca, Corvia, and Pfizer and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk,Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya and Ultromics. C.S.P.L. has received research support from Novo Nordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape\/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and is a co-founder and non-executive director of Us2.ai. F.Z. reports personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea and Us2.ai, having stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal and Eshmoun Clinical research and being the founder of Cardiovascular Clinical Trialists. K.F.D. reports that his employer, the University of Glasgow, has been remunerated by AstraZeneca for his work on clinical trials, and he has received speaker fees from AstraZeneca, Boehringer Ingelheim, Pharmacosomos and Translational Medicine Academy; has served on advisory boards or performed consultancy for FIRE-1, Us2.ai and Bayer AG; holds stock in Us2.ai; has served on a Clinical Endpoint Committee for Bayer AG; and has received research grant support (paid to his institution) from AstraZeneca, Roche, Novartis and Boehringer Ingelheim. J.J.V.M. reports payments through Glasgow University from work on clinical trials, consulting and grants from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK and Novartis; personal consultancy fees from Alnylam Pharmaceuticals,Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, IonisPharmaceuticals, Novartis, Regeneron Pharmaceuticals, River 2 Renal Corp., British Heart Foundation, National Institute for Health \u2013 National Heart Lung and Blood Institute (NIH-NHLBI), Boehringer Ingelheim, SQ Innovations and Catalyze Group; and personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd., Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd., Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd., Lupin Pharmaceuticals, Medscape\/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group and Translational Medicine Academy. He serves on a DSMB for WIRB-CopernicusGroup Clinical Inc, and he is a director of Global Clinical Trial Partners Ltd. S.D.S. has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH\/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos and Us2.ai and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, CardiacDimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros and Valo.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}