Advances in targeting LDL cholesterol: PCSK9 inhibitors and beyond

There is a direct relationship between the duration and level of exposure to low density lipoprotein cholesterol (LDL-C) levels over one's lifespan and cardiovascular events. Early treatment to lower elevated LDL-C is crucial for better outcomes with multiple therapies currently available to reduce atherogenic lipoproteins. Statins remain the foundation of LDL-C lowering therapy as one of the most cost-effective drugs to reduce atherosclerotic events (ASCVD) and mortality. Nonetheless, LDL-driven goal attainment remains suboptimal globally, highlighting a considerable need for non-statin therapies to address residual risk related to statin intolerance, non-adherence, and inherited lipoprotein disorders. LDL-C lowering interventions beyond statins include ezetimibe, PCSK9 monoclonal antibodies, inclisiran and bempedoic acid with specific guideline recommendations as to when to consider each. For patients with homozygous familial hypercholesterolemia requiring more advanced therapy, lomitapide and evinacumab are available, providing mechanisms that are not LDL receptor dependent. Lipoprotein apheresis remains an effective option for clinical familial hypercholesterolemia as well as elevated lipoprotein (a). There are investigational therapies being explored to add to our current armamentarium including CETP inhibitors, a third-generation PCSK9 inhibitor (small recombinant fusion protein oral PCSK9 inhibitor) and gene editing which aims to directly restore or disrupt genes of interest at the DNA level. This article is a brief review of the pharmacotherapy options beyond statins for lowering LDL-C and their impact on ASCVD risk reduction. Our primary aim is to guide physicians on the role these therapies play in achieving appropriate LDL-C goals, with an algorithm of when to consider each based on efficacy, safety and outcomes.