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Here we evaluated whole-exome sequencing data from the randomized DECLARE-TIMI 58 trial, in which adults with type 2 diabetes and increased cardiovascular risk were randomized to dapagliflozin or placebo treatment. Pathogenic or likely pathogenic variants (P\/LP) in high-confidence cardiomyopathy genes were identified, and treatment effects on hospitalization for HF (HHF) were compared between carriers of such variants and noncarriers. Among 12,685 patients for whom sequence data were obtained, 121 carried a cardiomyopathy variant (76 dilated cardiomyopathy, 25 hypertrophic cardiomyopathy and 25 arrhythmogenic cardiomyopathy). Over a median follow-up of 4.2\u2009years, dapagliflozin lowered the risk of HHF more strongly in carriers (hazard ratio 0.18, 95% confidence interval 0.04\u20130.86) than in noncarriers (hazard ratio 0.70, 95% confidence interval 0.57\u20130.86;\n                    <jats:italic>P<\/jats:italic>\n                    interaction 0.03). Absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (\n                    <jats:italic>P<\/jats:italic>\n                    interaction 0.03). Most carriers (82%) had no prior HF, and in carriers without prior HF, treatment with dapagliflozin reduced the absolute risk of HHF by 12.8%, compared with a reduction of 0.6% in noncarriers (\n                    <jats:italic>P<\/jats:italic>\n                    interaction 0.01). The findings from this cohort of older and high-risk patients raise the possibility that SGLT2 inhibitor treatment should be started early to prevent HF in individuals who carry P\/LP cardiomyopathy variants. These results need to be confirmed in a prospective, dedicated trial of preventive HF treatments in carriers of P\/LP cardiomyopathy-associated variants.\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04439-x","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T09:05:04Z","timestamp":1780909504000},"page":"2288-2293","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6164-4617","authenticated-orcid":false,"given":"Nicholas A.","family":"Marston","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8113-733X","authenticated-orcid":false,"given":"Shinwan","family":"Kany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6371-1334","authenticated-orcid":false,"given":"Giorgio E. M.","family":"Melloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1605-9782","authenticated-orcid":false,"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7208-1047","authenticated-orcid":false,"given":"Frederick K.","family":"Kamanu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6550-8329","authenticated-orcid":false,"given":"Yi-Pin","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6429-5149","authenticated-orcid":false,"given":"Joel T.","family":"R\u00e4m\u00f6","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itamar","family":"Raz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Wiviott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick T.","family":"Ellinor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc S.","family":"Sabatine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4712-3206","authenticated-orcid":false,"given":"Christian T.","family":"Ruff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"4439_CR1","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/nrcardio.2016.25","volume":"13","author":"B Ziaeian","year":"2016","unstructured":"Ziaeian, B. & Fonarow, G. C. Epidemiology and aetiology of heart failure. Nat. Rev. Cardiol. 13, 368\u2013378 (2016).","journal-title":"Nat. Rev. Cardiol."},{"key":"4439_CR2","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1056\/NEJMoa1812389","volume":"380","author":"SD Wiviott","year":"2019","unstructured":"Wiviott, S. D. et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 380, 347\u2013357 (2019).","journal-title":"N. Engl. J. Med."},{"key":"4439_CR3","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","volume":"381","author":"JJV McMurray","year":"2019","unstructured":"McMurray, J. J. V. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 381, 1995\u20132008 (2019).","journal-title":"N. Engl. J. Med."},{"key":"4439_CR4","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":"4439_CR5","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1161\/CIRCULATIONAHA.113.002767","volume":"128","author":"PMA Alexander","year":"2013","unstructured":"Alexander, P. M. A. et al. Long-term outcomes of dilated cardiomyopathy diagnosed during childhood: results from a national population-based study of childhood cardiomyopathy. Circulation 128, 2039\u20132046 (2013).","journal-title":"Circulation"},{"key":"4439_CR6","doi-asserted-by":"publisher","first-page":"3503","DOI":"10.1093\/eurheartj\/ehad194","volume":"44","author":"E Arbelo","year":"2023","unstructured":"Arbelo, E. et al. 2023 ESC Guidelines for the management of cardiomyopathies: developed by the task force on the management of cardiomyopathies of the European Society of Cardiology (ESC). Eur. 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Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci. Transl. Med. 7, 270ra6 (2015).","journal-title":"Sci. Transl. Med."},{"key":"4439_CR30","doi-asserted-by":"publisher","first-page":"2528","DOI":"10.1161\/CIRCULATIONAHA.119.040130","volume":"139","author":"ET Kato","year":"2019","unstructured":"Kato, E. T. et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. 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(CPC Clinical Research) and Viz.ai, and honoraria for lectures\/CME Programs from Amgen, Illumina, and Medical Education Speakers Network (MESN). S.D.W. is an employee of the trial sponsor, AstraZeneca. P.T.E. receives sponsored research support from Bayer AG, Bristol Myers Squibb, Pfizer and Novo Nordisk; he has also served on advisory boards or consulted for Bayer AG. M.S.S. reports research grant support through Brigham and Women\u2019s Hospital from Abbott, Amgen, Anthos Therapeutics, Inc., AstraZeneca, Beijing Inno Medicine, Boehringer Ingelheim, Daiichi Sankyo, Ionis, Marea, Merck, Novartis, Pfizer, Saghmos Therapeutics and Verve Therapeutics, and consulting for Amgen, AMPEL BioSolutions, Anthos Therapeutics, Inc., AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Dr. Reddy\u2019s Laboratories, Fibrogen, General Medicines, Merck, Moderna, Novo Nordisk, Precision BioSciences, Silence Therapeutics and TigerMed. C.T.R. reports research grants through Brigham and Women\u2019s Hospital from Anthos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis and has received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen and Pfizer. Furthermore, N.A.M., G.E.M.M., F.K.K., Y.-P.L., M.S.S. and C.T.R. are members of the TIMI (Thrombolysis in Myocardial Infarction) Study Group, which has received institutional research grant support through Brigham and Women\u2019s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Cleerly, Inc., Daiichi Sankyo, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Saghmos Therapeutics, Inc., Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc., and Zora Biosciences. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}