Incretin-based cardiovascular protection extends beyond diabetes, driven by GLP-1RAs and multi-agonists

Initially developed for type 2 diabetes (T2DM), incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have profoundly reshaped cardiometabolic medicine. Traditional approaches often focused on glycemic control, but a critical gap existed in understanding and leveraging the direct cardiovascular benefits of these agents. This review addresses the paradigm shift, highlighting how GLP-1 RAs and emerging multi-agonists provide significant cardiovascular protection beyond their glucose-lowering effects, impacting conditions like atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and heart failure with preserved ejection fraction (HFpEF), even in non-diabetic populations.

This critical review synthesized a comprehensive body of evidence, including cardiovascular outcome trials (CVOTs), mechanistic studies, meta-analyses, guideline recommendations, and regulatory developments. The search encompassed literature available up to April 30, 2026, focusing on GLP-1 RAs and dual/triple incretin-based agonists. The review aimed to consolidate findings on cardiovascular protection, assess the independence of this benefit from diabetes status, and evaluate the evolving therapeutic landscape, including oral peptide and non-peptide formulations, and combination strategies with SGLT2 inhibitors.

Incretin-based therapies consistently reduce major adverse cardiovascular events (MACE) in patients with T2DM and established ASCVD. Notably, semaglutide 2.4 mg has expanded this evidence to individuals with overweight or obesity and established CVD in the absence of diabetes. Dedicated trials have further demonstrated benefits in chronic kidney disease (CKD), obesity-related heart failure with preserved ejection fraction (HFpEF), and symptomatic peripheral artery disease (PAD). The review concludes that incretin-based cardiovascular protection is both biologically plausible and clinically reproducible. This benefit is now considered independent of diabetes as the defining therapeutic context, marking a significant paradigm shift. The magnitude of benefit, however, varies considerably by molecule, dose, population, comparator, and endpoint hierarchy. > GLP-1 RAs with proven outcome benefit, such as liraglutide (LEADER) and semaglutide (SUSTAIN-6, SELECT), should be prioritized in patients with ASCVD or obesity with established CVD.