Incretin-based cardiovascular protection beyond diabetes: evidence, mechanisms, and therapeutic frontiers from GLP-1 receptor agonists to multi-agonist therapy

Incretin-based therapy has moved from glycaemic control into the centre of cardiometabolic medicine. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) consistently reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2DM) and established atherosclerotic cardiovascular disease (ASCVD), while semaglutide 2.4 mg has extended the evidence base to people with overweight or obesity and established cardiovascular disease in the absence of diabetes. Dedicated trials have further expanded the clinical landscape to chronic kidney disease (CKD), obesity-related heart failure with preserved ejection fraction (HFpEF), and symptomatic peripheral artery disease (PAD). Concurrently, dual and triple incretin-based agonists, oral peptide and non-peptide formulations, and combination strategies with sodium-glucose cotransporter-2 (SGLT2) inhibitors and non-steroidal mineralocorticoid receptor antagonists are reshaping treatment algorithms. This critical review synthesizes cardiovascular outcome trials (CVOTs), mechanistic studies, meta-analyses, guideline recommendations, and regulatory developments available up to 30 April 2026. The central conclusion is that incretin-based cardiovascular protection is biologically plausible and clinically reproducible. Critically, this benefit is now independent of diabetes as the defining therapeutic context-a paradigm shift with broad implications for cardiovascular practice. Nevertheless, the magnitude of benefit varies considerably by molecule, dose, population, comparator, and endpoint hierarchy; mediation analyses do not precisely quantify direct cardioprotection; and cardiovascular outcome evidence for newer multi-agonists and oral non-peptide GLP-1 RAs remains incomplete. Interpretation therefore requires a balanced evidence framework: GLP-1 RAs with proven outcome benefit should be prioritized in patients with ASCVD (e.g., LEADER, SUSTAIN-6, HARMONY Outcomes), obesity with established CVD (SELECT), CKD (FLOW), or obesity-related HFpEF (STEP-HFpEF) when supported by trial data and regulatory indications, whereas next-generation agents should be evaluated according to completed CVOTs rather than weight-loss efficacy alone. Remaining research priorities include defining weight-independent mechanisms, optimizing combination therapy, identifying biomarker-defined responders, preserving lean mass during high-efficacy weight loss, and ensuring equitable global access.