Journal Article

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

Jakobsen, Janus C, Hove, Jens Dahlgaard, Dirksen, Carsten, Grand, Johannes, Wisborg, Frederik Dencker, Sillassen, Christina Dam Bjerregaard, El-Sheikh, Mohammed, Lee, Matthew Meng Yang

2025

Overview

BackgroundIncretin-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—particularly in patients with and without a history of heart failure (HF).Methods and analysisWe 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).Ethics and disseminationAs 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.PROSPERO registration numberCRD420251003374.

• Publisher: British Medical Journal Publishing Group,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Body mass index / Cardiac arrhythmia / Cardiovascular Disease / Cardiovascular Medicine / Clinical trials / Diabetes Mellitus, Type 2 - complications / Diabetes Mellitus, Type 2 - drug therapy / Drug Therapy / Drugs / Ejection fraction / FDA approval / Glucagon / Glucagon-Like Peptide-1 Receptor Agonists / Glucose / Heart failure / Heart Failure - complications / Heart Failure - drug therapy / Heart rate / Hospitalization / Humans / Incretins - pharmacology / Incretins - therapeutic use / Meta-Analysis / Meta-Analysis as Topic / Obesity / Overweight / Peptides / Protocol / Randomized Controlled Trials as Topic / Research Design / Safety / Systematic Review / Systematic Reviews as Topic / Weight control