Abstract
As the global population ages and cardiovascular risk factors rise, we can expect a continued increase in atherosclerotic disease. Low-density lipoprotein cholesterol (LDL-C) reduction is a cornerstone of cardiovascular risk reduction with strong, causal evidence indicating that the greatest benefit is derived from early and large decreases in LDL-C. Despite the adoption of statins as the backbone of lipid-therapy regimens, numerous studies and registry analyses reveal our collective inability to achieve LDL-C goals in high-risk patients. Combination therapy with ezetimibe has been shown to result in statistically significant decreases in LDL-C level, atheroma volume, and cardiovascular adverse event rates. A major barrier to implementing an upfront combination therapy approach is the perceived side effects from therapeutic agents although multiple studies show that a therapeutic patient-physician relationship could overcome this issue. Novel agents such as PCSK-9 inhibitors, bempedoic acid, and inclisiran have the potential to achieve similar outcomes although additional research is needed regarding the cost effectiveness of these approaches. Despite these hurdles, there is a role for the newer agents early in the disease course of high-risk patients such as those with markedly elevated LDL-C >190 mg/dL and FH. The implementation of upfront combination therapy, especially in high-risk patients, will decrease clinical inertia while allowing for earlier consideration of newer, effective agents to decrease cardiovascular burden.