{
  "abstract": "Background Cardiovascular diseases, overweight, type 2 diabetes and chronic kidney disease increase the risk of cardiovascular events.Glucagon-like peptide-1 analogues are recommended by the European Society of Cardiology and the American College of Cardiology to lower the risk of death and progression of cardiovascular disease in patients with cardiovascular disease and type 2 diabetes. Semaglutide, tirzepatide and liraglutide are approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of type 2 diabetes mellitus and overweight. CagriSema is currently not approved, but several phase III trials are ongoing.No previous systematic review has investigated the effects of semaglutide, tirzepatide, CagriSema and liraglutide, which may not be disease-specific, on hard binary outcomes for all trial populations at increased risk of cardiovascular events.Methods and analyses We will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded, Conference Proceedings Citation Index—Science) and clinical trial registries from their inception and onwards to identify relevant randomised trials. We expect to perform the literature search in December 2025. Two review authors will independently extract data and assess the risk of bias. We will include randomised trials assessing the effects of semaglutide, tirzepatide, CagriSema and/or liraglutide in participants with an increased risk of cardiovascular events. The primary outcome will be all-cause mortality. Secondary outcomes will be myocardial infarction, stroke and all-cause hospitalisation. Data will be synthesised by aggregate data meta-analyses, Trial Sequential Analyses and network meta-analysis, risk of bias will be assessed with Cochrane Risk of Bias tool V. 2, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations and the Confidence in Network Meta-Analysis approach.Ethics and dissemination This protocol does not present any results. Findings of this systematic review will be published in international peer-reviewed scientific journals.PROSPERO registration number CRD42024623312.",
  "authors": [
    {
      "affiliations": [
        "Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark",
        "Department of Cardiology and Endocrinology, Slagelse Hospital, Slagelse, Denmark",
        "Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark"
      ],
      "name": "Christina Dam Bjerregaard Sillassen"
    },
    {
      "affiliations": [
        "Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark",
        "Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark"
      ],
      "name": "Pascal Faltermeier"
    },
    {
      "affiliations": [
        "Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark"
      ],
      "name": "Johanne Juul Petersen"
    },
    {
      "affiliations": [
        "Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark"
      ],
      "name": "Caroline Barkholt Kamp"
    },
    {
      "affiliations": [
        "Department of Cardiology, Copenhagen University Hospital - Amager-Hvidovre Hospital, Hvidovre, Denmark"
      ],
      "name": "Johannes Grand"
    },
    {
      "affiliations": [
        "Department of Cardiology, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark",
        "Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Helena Dominguez"
    },
    {
      "affiliations": [
        "Innovation and Research Centre for Multimorbidity, Slagelse Hospital, Slagelse, Denmark",
        "Section of General Practice, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Anne Frølich"
    },
    {
      "affiliations": [
        "Department of Cardiology and Endocrinology, Slagelse Hospital, Slagelse, Denmark",
        "Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark"
      ],
      "name": "Peter Haulund Gæde"
    },
    {
      "affiliations": [
        "Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark",
        "Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark"
      ],
      "name": "Christian Gluud"
    },
    {
      "affiliations": [
        "Centre for Anaesthesiological Research, Department of Anaesthesiology, Zealand University Hospital, Køge, Denmark",
        "Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Ole Mathiesen"
    },
    {
      "affiliations": [
        "Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark",
        "Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark"
      ],
      "name": "Janus C Jakobsen"
    }
  ],
  "title": "Effects of glucagon-like peptide-1 analogues on hard binary outcomes for patients at increased risk of cardiovascular events: a protocol for a systematic review with network meta-analysis and Trial Sequential Analysis",
  "uid": "982956f1-364b-595f-8d3b-a60b901453c0"
}