{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T22:00:27Z","timestamp":1794088827720,"version":"4.8.0"},"reference-count":105,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2025,9,21]],"date-time":"2025-09-21T00:00:00Z","timestamp":1758412800000},"content-version":"unspecified","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,9,5]]},"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Incretin-based drugs, including glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)\/GLP-1 RAs, are increasingly used in the management of type 2 diabetes mellitus and obesity. While these agents have shown cardiovascular benefits, their effects on both cardiovascular outcomes and cardiac structure and function remain uncertain\u2014particularly in patients with and without a history of heart failure (HF).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>We will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded (SCI-EXPANDED) and Conference Proceedings Citation Index-Science (CPCI-S)), as well as clinical trial registries from their inception and onwards to identify relevant randomised trials. The literature search is scheduled for July 2025. Two review authors will independently extract data and assess risk of bias. We will include randomised controlled trials assessing the effects of cagrilintide\/semaglutide, liraglutide, semaglutide and tirzepatide in patients with and without a history of HF. The primary outcome will be cardiovascular mortality. Secondary outcomes will include HF hospitalisation, myocardial infarction, stroke, heart rate, systolic blood pressure, N-terminal pro B-type natriuretic peptide, left ventricular ejection fraction, left ventricular end-diastolic volume and left ventricular end-systolic volume. Data will be synthesised by aggregate data meta-analyses and trial sequential analysis. Risk of bias will be assessed with the Cochrane Risk of Bias tool, version 2, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>As this study is a systematic review based on secondary analysis of published data, ethical approval is not required. Findings will be published in international peer-reviewed scientific journals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PROSPERO registration number<\/jats:title>\n                    <jats:p>CRD420251003374.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-103668","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T02:30:58Z","timestamp":1758508258000},"page":"e103668","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Cardiovascular effects of incretin-based drugs in patients with and without a history of heart failure: a protocol for a systematic review, meta-analysis and trial sequential analysis of randomised controlled trials"],"prefix":"10.1136","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0549-2203","authenticated-orcid":false,"given":"Mohammed","family":"El-Sheikh","sequence":"first","affiliation":[{"name":"Department of Cardiology, Copenhagen University Hospital, Amager and Hvidovre Hospital, Hvidovre, Denmark, Hvidovre Hospital, Hvidovre, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9247-5245","authenticated-orcid":false,"given":"Christina Dam Bjerregaard","family":"Sillassen","sequence":"additional","affiliation":[{"name":"Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital \u0336 Rigshospitalet, Copenhagen, Denmark, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Cardiology and Endocrinology, Slagelse Hospital, Slagelse, Denmark"},{"name":"Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark, University of Southern Denmark, Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik Dencker","family":"Wisborg","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Copenhagen University Hospital, Amager and Hvidovre Hospital, Hvidovre, Denmark, Hvidovre Hospital, Hvidovre, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens Dahlgaard","family":"Hove","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Copenhagen University Hospital, Amager and Hvidovre Hospital, Hvidovre, Denmark, Hvidovre Hospital, Hvidovre, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Dirksen","sequence":"additional","affiliation":[{"name":"Department of Respiratory Diseases and Endocrinology, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark, Hvidovre Hospital, Hvidovre, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Hvidovre Hospital, Hvidovre, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew Meng Yang","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom, University of Glasgow, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janus C","family":"Jakobsen","sequence":"additional","affiliation":[{"name":"Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital \u0336 Rigshospitalet, Copenhagen, Denmark, Rigshospitalet, Copenhagen, Denmark"},{"name":"Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark, University of Southern Denmark, Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5511-4668","authenticated-orcid":false,"given":"Johannes","family":"Grand","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Copenhagen University Hospital, Amager and Hvidovre Hospital, Hvidovre, Denmark, Hvidovre Hospital, Hvidovre, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,9,21]]},"reference":[{"key":"2025111921301028000_15.9.e103668.1","doi-asserted-by":"crossref","DOI":"10.1016\/j.molmet.2020.101102","article-title":"GLP-1 receptor agonists in the treatment of type 2 diabetes - 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REDEFINE 1: efficacy and safety of cagrilintide s.c. 2.4 milligram (mg) in combination with semaglutide subcutaneous (s.c). 2.4 mg (cagrisema s.c. 2.4 mg) once-weekly in participants with overweight or obesity. ClinicaltrialsGov; 2025. Available: https:\/\/clinicaltrials.gov\/study\/NCT05567796 [Accessed 11 Feb 2025]."},{"key":"2025111921301028000_15.9.e103668.34","unstructured":"Novo Nordisk . REDEFINE 2: efficacy and safety of cagrilintide s.c. 2.4 mg in combination with semaglutide s.c. 2.4 mg (cagrisema s.c. 2.4 mg) once-weekly in participants with overweight or obesity and type 2 diabetes. clinicaltrials.gov; 2025. Available: https:\/\/clinicaltrials.gov\/study\/NCT05394519 [Accessed 11 Feb 2025]."},{"key":"2025111921301028000_15.9.e103668.35","unstructured":"Novo Nordisk . REDEFINE 6: efficacy and safety of cagrilintide 2.4 mg s.c. in combination with semaglutide 2.4 mg s.c. (cagrisema s.c. 2.4 mg) once-weekly compared to tirzepatide 15 mg s.c. once-weekly in participants with obesity. ClinicaltrialsGov; 2024. Available: https:\/\/clinicaltrials.gov\/study\/NCT06131437 [Accessed 11 Feb 2025]."},{"key":"2025111921301028000_15.9.e103668.36","unstructured":"Novo Nordisk . Efficacy and safety of cagrilintide 2.4 mg s.c. in combination with semaglutide 2.4 mg s.c. (cagrisema s.c. 2.4 mg) once-weekly compared to tirzepatide 15 mg s.c. once-weekly in participants with obesity. ClinicaltrialsGov; 2024. Available: https:\/\/clinicaltrials.gov\/study\/NCT06131437 [Accessed 11 Feb 2025]."},{"key":"2025111921301028000_15.9.e103668.37","unstructured":"Novo Nordisk . REIMAGINE 2: efficacy and safety of co-administered cagrilintide and semaglutide (cagrisema) s.c. in doses 2.4;\u202f;2.4 mg and 1.0;1.0 mg once weekly versus semaglutide 2.4 mg and 1.0 mg, cagrilintide 2.4 mg and placebo in participants with type 2 diabetes inadequately controlled on metformin with or without an sglt2 inhibitor. clinicaltrials.gov; 2025. 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