Beyond statins: New pharmacological targets to decrease LDL-cholesterol and cardiovascular events

Abstract

The pharmacological treatment of dyslipidemia, a major modifiable risk factor for developing atherosclerotic cardiovascular disease (ASCVD), remains a debated and controversial issue, not only in terms of the most appropriate therapeutic range for lipid levels, but also with regard to the optimal strategy and sequence approach (stepwise vs upstream therapy). Current treatment guidelines for the management of dyslipidemia focus on the intensity of low-density lipoprotein cholesterol (LDL-C) reduction, stratified according to risk for developing ASCVD. Beyond statins and ezetimibe, different medications targeting LDL-C have been recently approved by regulatory agencies with potential innovative mechanisms of action, including proprotein convertase subtilisin/kexin type 9 modulators (monoclonal antibodies such as evolocumab and alirocumab; small interfering RNA molecules such as inclisiran), ATP-citrate lyase inhibitors (bempedoic acid), angiopoietin-like 3 inhibitors (evinacumab), and microsomal triglyceride transfer protein inhibitors (lomitapide). An understanding of their pharmacological aspects, benefit-risk profile, including impact on hard cardiovascular endpoints beyond LDL-C reduction, and potential advantages from the patient perspective (e.g., adherence) - the focus of this evidence-based review - is crucial for practitioners across medical specialties to minimize therapeutic inertia and support clinical practice.