Incretin analogues as cardiovascular agents: a state-of-the-art review

Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist tirzepatide have evolved over the past decade from glucose-lowering antidiabetic agents into a cardiovascular drug class with proven outcome benefit across multiple clinical scenarios. This state-of-the-art review synthesizes the cardiovascular evidence base for incretin analogues, organized by clinical scenario, and addresses the structural challenges that constrain their deployment in low- and middle-income countries (LMICs). We review the pharmacology and proposed cardiovascular mechanisms, including direct effects on the vascular endothelium, macrophage inflammation, and epicardial adipose tissue, alongside indirect benefits mediated by weight loss, glycemic control, and blood pressure reduction. We summarize the evidence in five clinical scenarios: type 2 diabetes with established atherosclerotic cardiovascular disease or high cardiovascular risk; overweight or obesity with established cardiovascular disease but without diabetes; obesity-related heart failure with preserved ejection fraction; chronic kidney disease; and symptomatic peripheral artery disease. Pipeline agents (retatrutide, CagriSema, survodutide, orforglipron, zenagamtide, and MariTide) are reviewed alongside their ongoing cardiovascular outcome trials. A dedicated section examines the global access perspective, including the disproportionately high burden of cardiometabolic disease in LMICs, the limited representation of regional populations in pivotal trials, and the structural barriers of cost and reimbursement that constrain access. We close with a practical algorithm for the clinician, an honest assessment of evidence gaps, and a calibrated outlook on the next generation of incretin-based cardiovascular therapy.