The risk of cardiovascular disease is significantly increased by both type 2 diabetes mellitus (T2DM) and obesity through overlapping pathways involving insulin resistance, dyslipidemia, systemic inflammation, and endothelial dysfunction. Tirzepatide, the first dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, has shown significant glycemic and weight-reducing effects and is increasingly recognized as a cardiometabolic therapy that extends beyond glucose control. This narrative review summarizes clinical and translational evidence about the cardiovascular and metabolic benefits of tirzepatide and the biologic mechanisms that may underpin its effects. Tirzepatide has consistently shown high improvements in key indicators of glycemic control and body weight across the SURPASS program in patients with T2DM and the SURMOUNT program in patients with obesity. Benefits include marked reduction in glycated hemoglobin and cardiovascular risk factors, such as systolic and diastolic blood pressure, atherogenic lipid parameters, visceral adiposity, and several inflammatory biomarkers. Dual incretin signaling seems to increase endothelial function by enhancing the bioavailability of nitric oxide, reducing oxidative stress, inhibiting pro-inflammatory pathways such as nuclear factor kappa B, and favorably modulating adipokine profiles, collectively supporting cardiovascular protection. Promising data suggest symptomatic and functional improvements in obesity-related heart failure with preserved ejection fraction. Reductions in major adverse cardiovascular events are currently under investigation in dedicated outcome trials, including the SURPASS Cardiovascular Outcomes Trial. Overall, tirzepatide provides broad cardiometabolic benefits, making it a promising treatment in the changing landscape of cardiometabolic disease management.
