{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:16:39Z","timestamp":1783426599235,"version":"3.54.6"},"reference-count":33,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) usually coexist and are related to increased morbidity and mortality. Cardiovascular benefits have been demonstrated by drugs such as sodium-glucose cotransporter-2 inhibitors (SGLT2i) and GLP-1 receptor agonists including the dual GIP\/GLP-1 receptor agonist tirzepatide (collectively, incretin-based therapies); however, their relative effectiveness in patients with concomitant AF and HFpEF remains undefined. Methods: We conducted a retrospective, propensity score-matched cohort study utilizing the TriNetX Global Collaborative Network. Adults with AF or atrial flutter with a diagnosis of HFpEF who initiated incretin-based therapies (GLP-1 receptor agonists or dual GLP-1\/GIP receptor agonists) or SGLT2i were included; index medication was required to be initiated within 30 days of a qualifying AF\/HFpEF diagnosis. 1:1 matching was performed based on baseline medications, demographics, and comorbidities. Co-primary outcomes were all-cause mortality, inpatient visits, and emergency department (ED) visits at 1 year. Secondary outcomes included myocardial infarction, ischemic stroke, acute kidney injury, transient ischemic attack, major adverse cardiovascular events (MACE; all-cause mortality\/MI\/stroke composite), and AF-related procedures. Agent-specific subgroup analyses were performed for semaglutide and tirzepatide separately. Sensitivity analyses were conducted at 6 months and 2 years. Results: 7624 patients were included in each cohort after matching (mean age: 70.8 years; 52% women). At 1 year, incretin-based therapy was associated with lower all-cause mortality (5.3% vs. 7.3%, HR 0.721, 95% CI 0.634\u20130.820; p &lt; 0.001), fewer inpatient visits (30.0% vs. 37.4%, HR 0.743, 95% CI 0.702\u20130.787; p &lt; 0.001), and no statistically significant difference in ED visits (27.0% vs. 28.0%; HR 0.946, 95% CI 0.888\u20131.007; p = 0.081) compared with SGLT2i. Incretin-based therapy was also associated with lower risk of MACE (HR 0.709), acute kidney injury (HR 0.751), myocardial infarction (HR 0.583), catheter ablation (HR 0.685), and electrical cardioversion (HR 0.472). No significant differences were observed in ischemic stroke or transient ischemic attack. These findings were broadly consistent at 6-month and 2-year follow-up, and directionally consistent in agent-specific subgroup analyses of semaglutide and tirzepatide. Conclusions: In this large propensity-matched cohort of patients with AF and HFpEF, initiation of incretin-based therapy (GLP-1 receptor agonists or dual GLP-1\/GIP receptor agonists) was associated with lower all-cause mortality, fewer inpatient visits, and reduced cardiovascular events compared with SGLT2i. These findings, while subject to observational limitations, suggest potential benefits of incretin-based therapy in this high-risk population and support the need for prospective comparative trials.<\/jats:p>","DOI":"10.3390\/jcm15134992","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T08:45:20Z","timestamp":1782722720000},"page":"4992","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GLP-1 Receptor Agonists or Dual GLP-1\/GIP Receptor Agonists vs. SGLT2 Inhibitors in Patients with Atrial Fibrillation and HFpEF: A Propensity-Matched Real-World Analysis"],"prefix":"10.3390","volume":"15","author":[{"given":"Faizan","family":"Ahmed","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Hackensack Meridian Health, Jersey Shore University Medical Center, Neptune, NJ 07753, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0278-3996","authenticated-orcid":false,"given":"Najam","family":"Gohar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Ameer-ud-Din Medical College, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4020-8775","authenticated-orcid":false,"given":"Madeeha","family":"Shafqat","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Geisinger Medical Center, Danville, PA 17822, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8229-0245","authenticated-orcid":false,"given":"Daniel","family":"Aziz","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Gagnon Cardiovascular Institute, Morristown Medical Center, Morristown, NJ 07960, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4008-8912","authenticated-orcid":false,"given":"Mohammad Omar","family":"Butt","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Memorial Satilla Health, Waycross, GA 31501, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8968-861X","authenticated-orcid":false,"given":"Hassaan","family":"Abid","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Indiana University School of Medicine, Muncie, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1700-9131","authenticated-orcid":false,"given":"Haziq","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Shaikh Khalifa Bin Zayed Al Nahyan Medical and Dental College, Lahore 54600, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4886-5528","authenticated-orcid":false,"given":"Mohammad Saad","family":"Saeeduddin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, St. Mary Medical Center, Langhorne, PA 19047, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9452-6877","authenticated-orcid":false,"given":"Ch M Umer","family":"Zaman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Ameer-ud-Din Medical College, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7057-9975","authenticated-orcid":false,"given":"Haris Bin","family":"Tahir","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Lahore General Hospital, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9895-7170","authenticated-orcid":false,"given":"Muhammad","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qaiser","family":"Shahzad","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Winchester Medical Center, Winchester, VA 22601, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayesha","family":"Zulfiqar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6836-4490","authenticated-orcid":false,"given":"Amro","family":"Taha","sequence":"additional","affiliation":[{"name":"Division of Cardiology, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swapnil","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hackensack Meridian Health, Jersey Shore University Medical Center, Neptune, NJ 07753, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eran S.","family":"Zacks","sequence":"additional","affiliation":[{"name":"Department of Electrophysiology, Hackensack Meridian Health, Jersey Shore University Medical Center, Neptune, NJ 07753, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ijcard.2018.02.007","article-title":"Atrial fibrillation and heart failure with preserved ejection fraction: Insights on a unique clinical phenotype from a nationally-representative United States cohort","volume":"266","author":"Goyal","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.1111\/jce.16625","article-title":"Atrial Fibrillation (AF) and Heart Failure with Preserved Ejection Fraction (HFpEF): Advances and Challenges","volume":"36","author":"Saksena","year":"2025","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_3","unstructured":"Padda, I.S., Mahtani, A.U., and Parmar, M. (2025). Sodium-Glucose Transport 2 (SGLT2) Inhibitors. StatPearls, StatPearls Publishing LLC."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Wu, Q., Zhang, J., Zhang, F., and Li, D. (2025). SGLT2 inhibitors as metabolic modulators: Beyond glycemic control in type 2 diabetes. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1601633"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ramadan, M.M., Jawish, M.K., Tamim, O., Abdelbary, M.T., Al-Refai, N.H., Hady, S.M., A Salama, S., Alhaboobi, Z.H., A Abd-Alsamad, Y., and Alsabea, H.H. (2025). Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors in Atrial Fibrillation: Clinical Implications, Mechanisms, and Therapeutic Potential. Cureus, 17.","DOI":"10.7759\/cureus.96689"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s12933-021-01293-8","article-title":"Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: A systematic review and meta-analysis","volume":"20","author":"Li","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mullur, N., Morissette, A., Morrow, N.M., and Mulvihill, E.E. (2024). GLP-1 receptor agonist-based therapies and cardiovascular risk: A review of mechanisms. J. Endocrinol., 263.","DOI":"10.1530\/JOE-24-0046"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bykova, A., Serova, M., Chashkina, M., Kosharnaya, R., Salpagarova, Z., Andreev, D., and Giverts, I. (2024). Glucagon-like Peptide-1 Receptor Agonists in the Context of Pathophysiology of Diverse Heart Failure with Preserved Ejection Fraction Phenotypes: Potential Benefits and Mechanisms of Action. Card. Fail. Rev., 10.","DOI":"10.15420\/cfr.2024.06"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1056\/NEJMoa2410027","article-title":"Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity","volume":"392","author":"Packer","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1056\/NEJMoa2306963","article-title":"Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity","volume":"389","author":"Kosiborod","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1016\/j.jacc.2016.08.048","article-title":"Heart failure with preserved ejection fraction and atrial fibrillation: Vicious twins","volume":"68","author":"Kotecha","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1161\/CIRCULATIONAHA.119.042996","article-title":"Interdependence of atrial fibrillation and heart failure with a preserved ejection fraction reflects a common underlying atrial and ventricular myopathy","volume":"141","author":"Packer","year":"2020","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1016\/j.hrthm.2024.08.064","article-title":"Atrial fibrillation and heart failure with preserved ejection fraction \u201ctwindemic\u201d\u2014Shared root causes and treatment targets","volume":"22","author":"Habel","year":"2025","journal-title":"Heart Rhythm"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"Empagliflozin in heart failure with a preserved ejection fraction","volume":"385","author":"Anker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1056\/NEJMoa2206286","article-title":"Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction","volume":"387","author":"Solomon","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3640","DOI":"10.1093\/eurheartj\/ehad389","article-title":"Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction","volume":"44","author":"Pandey","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"De Lorenzi, A.B., Kaplinsky, E., Zambrano, M.R., Chaume, L.T., and Rosas, J.M. (2023). Emerging concepts in heart failure management and treatment: Focus on SGLT2 inhibitors in heart failure with preserved ejection fraction. Drugs Context, 12.","DOI":"10.7573\/dic.2022-7-1"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/S0140-6736(22)01429-5","article-title":"SGLT2 inhibitors in patients with heart failure: A comprehensive meta-analysis of five randomised controlled trials","volume":"400","author":"Vaduganathan","year":"2022","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1002\/ejhf.2861","article-title":"Empagliflozin in heart failure with preserved ejection fraction with and without atrial fibrillation","volume":"25","author":"Filippatos","year":"2023","journal-title":"Eur. J. Heart Fail."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jalil, J.E., Gabrielli, L., Ocaranza, M.P., MacNab, P., Fern\u00e1ndez, R., Grassi, B., Jofr\u00e9, P., Verdejo, H., Acevedo, M., and Cordova, S. (2024). New mechanisms to prevent heart failure with preserved ejection fraction using glucagon-like peptide-1 receptor agonism (GLP-1 RA) in metabolic syndrome and in type 2 diabetes: A review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084407"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s12933-025-02607-w","article-title":"The role of glucagon-like peptide-1 receptor (GLP-1R) agonists in enhancing endothelial function: A potential avenue for improving heart failure with preserved ejection fraction (HFpEF)","volume":"24","author":"Hullon","year":"2025","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/j.jacc.2024.08.023","article-title":"Atrial fibrillation and semaglutide effects in obesity-related heart failure with preserved ejection fraction: STEP-HFpEF program","volume":"84","author":"Verma","year":"2024","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1016\/j.jacc.2022.08.718","article-title":"Atrial fibrillation and dapagliflozin efficacy in patients with preserved or mildly reduced ejection fraction","volume":"80","author":"Butt","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/j.jacc.2023.03.393","article-title":"2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction: A report of the American College of Cardiology Solution Set Oversight Committee","volume":"81","author":"Kittleson","year":"2023","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1002\/ehf2.15223","article-title":"SGLT2i reduce arrhythmic events in heart failure patients with cardiac implantable electronic devices","volume":"12","author":"Mariani","year":"2025","journal-title":"ESC Heart Fail."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1603827","article-title":"Liraglutide and cardiovascular outcomes in type 2 diabetes","volume":"375","author":"Marso","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1056\/NEJMoa1607141","article-title":"Semaglutide and cardiovascular outcomes in patients with type 2 diabetes","volume":"375","author":"Marso","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1056\/NEJMoa2307563","article-title":"Semaglutide and cardiovascular outcomes in obesity without diabetes","volume":"389","author":"Lincoff","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/S2213-8587(19)30249-9","article-title":"Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials","volume":"7","author":"Kristensen","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1161\/CIRCULATIONAHA.123.067505","article-title":"Effects of semaglutide on symptoms, function, and quality of life in patients with heart failure with preserved ejection fraction and obesity: A prespecified analysis of the STEP-HFpEF trial","volume":"149","author":"Kosiborod","year":"2024","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jacc.2023.08.017","article-title":"2023 ACC\/AHA\/ACCP\/HRS guideline for the diagnosis and management of atrial fibrillation: A report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"83","author":"Joglar","year":"2024","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1056\/NEJMoa2206038","article-title":"Tirzepatide once weekly for the treatment of obesity","volume":"387","author":"Jastreboff","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1056\/NEJMoa2416394","article-title":"Tirzepatide as compared with semaglutide for the treatment of obesity","volume":"393","author":"Aronne","year":"2025","journal-title":"N. Engl. J. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/13\/4992\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:34:15Z","timestamp":1783424055000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/13\/4992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":33,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["jcm15134992"],"URL":"https:\/\/doi.org\/10.3390\/jcm15134992","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]}}}