Time to Combinatorial Regimens: SGLT2i and PCSK9i in High-Risk Cardio-Oncology Patients

Cardiometabolic complications represent a leading cause of morbidity and mortality among cancer survivors, who increasingly face a dual burden of residual oncologic risk and rising cardiovascular (CV) vulnerability. The shared pathophysiologic mechanisms linking cancer, dyslipidemia, insulin resistance, and chronic inflammation foster an environment conducive to accelerated atherosclerosis, heart failure, and metabolic dysregulation. Hyperglycemia and hyperlipidemia, frequently coexisting in long-term cancer survivors, especially those exposed to cardiotoxic chemotherapies, hormonal therapies, or corticosteroids, are key drivers of adverse CV outcomes. Despite this recognized risk, comprehensive preventive strategies in cardio-oncology remain limited and often rely on conventional therapies insufficient to fully address the complexity of cardiometabolic disease in this population. Notably, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have emerged as powerful tools in CV risk reduction. SGLT2i have demonstrated robust benefits in heart failure, renal protection, and glycemic control, while PCSK9i provide profound and sustained reductions in low-density lipoprotein cholesterol, with emerging pleiotropic anti-inflammatory and antiatherosclerotic effects. We propose that a combinatorial strategy integrating SGLT2i and PCSK9i may offer synergistic protection against the intertwined cardiometabolic risks seen in cancer survivors. This approach targets multiple mechanistic pathways, glucose and lipid metabolism, vascular inflammation, endothelial dysfunction, and organ remodeling, potentially redefining the standard of care in high-risk cardio-oncology populations. Further clinical investigation is warranted to validate this hypothesis and establish optimal therapeutic protocols.