Unmet Cardiovascular Risk Beyond LDL-C: A Perspective on Managing Residual Cardiovascular Risk

Despite major advances in lipid-lowering therapy and the widespread implementation of statins, ezetimibe, and PCSK9-targeted interventions, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Intensive lowering of low-density lipoprotein cholesterol (LDL-C) has substantially reduced cardiovascular events; however, a considerable degree of residual cardiovascular risk persists even among patients achieving very low LDL-C levels. This observation has shifted contemporary cardiovascular research toward a broader understanding of atherosclerosis as a multifactorial disorder involving triglyceride-rich lipoproteins (TRLs), apolipoprotein B (APOB)-containing particles, dysfunctional high-density lipoproteins (HDLs), lipoprotein(a) [Lp(a)], endothelial dysfunction, and chronic vascular inflammation. Emerging evidence further suggests that psychological and behavioral factors, including specific personality traits and chronic psychosocial stress, may contribute independently to cardiovascular disease susceptibility and outcomes. The present review summarizes emerging risk factors associated with residual cardiovascular risk and highlights novel therapeutic strategies beyond LDL-C lowering. Collectively, current evidence supports a transition from a simplistic LDL-C-centric paradigm toward a multiple risk factor approach for atherosclerosis prevention and treatment.