Cardiovascular protection beyond glucose lowering: GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonism in contemporary cardiology.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide have expanded from glucose-lowering therapy into cardiovascular medicine. In type 2 diabetes, several long-acting GLP-1RAs reduce major adverse cardiovascular events (MACE). SELECT extended this benefit to adults with established cardiovascular disease and overweight or obesity without diabetes, while SOUL demonstrated MACE reduction with oral semaglutide. SURPASS-CVOT established cardiovascular noninferiority of tirzepatide to dulaglutide but did not demonstrate superiority. Obesity-related heart failure with preserved ejection fraction (HFpEF) has emerged as a particularly responsive phenotype: semaglutide improves symptoms and physical function, whereas tirzepatide also reduces worsening heart failure events. FLOW further supports kidney and cardiovascular protection with semaglutide in type 2 diabetes and chronic kidney disease. Randomised human studies support effects on adiposity, haemodynamic burden, inflammation and cardiorenal outcomes, whereas endothelial, coronary microvascular and direct myocardial mechanisms remain less clinically validated. This Review integrates the current evidence, distinguishes randomised outcomes from observational and mechanistic signals, and provides a practical phenotype-directed treatment algorithm incorporating atherosclerotic cardiovascular disease, obesity, type 2 diabetes, chronic kidney disease, HFpEF, sodium-glucose cotransporter 2 inhibitor use and patient-specific treatment constraints. Current practice should be guided by indication-specific outcome evidence rather than weight-loss magnitude or indirect cross-trial comparisons.