Cardiovascular risk management beyond statins: review of new therapies available in Italy

Abstract

Background: Statins remain foundational in the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, despite optimal statin therapy, a significant residual risk of ASCVD persists, highlighting the need for novel lipid-lowering strategies targeting both low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins. Over the last decade, a new generation of pharmacological agents has been developed to enhance dyslipidemia management beyond traditional statins.

Main body: Bempedoic acid, a prodrug activated in the liver, inhibits ATP-citrate lyase (ACLY), an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway. This action reduces hepatic cholesterol synthesis and simultaneously upregulates LDL receptor expression, promoting enhanced LDL-C clearance. These dual actions provide a statin-independent approach to LDL-C reduction, particularly beneficial for patients with statin intolerance. In addition, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, including monoclonal antibodies and siRNA-based therapies, have shown robust LDL-C-lowering effects by preventing LDL receptor degradation, leading to a significant reduction in cardiovascular risk. Other innovative lipid-modifying approaches include antisense oligonucleotides targeting apolipoprotein C3, angiopoietin-like protein 3, and lipoprotein(a) [Lp(a)]-such as pelacarsen and olpasiran-which demonstrate promising results in addressing genetically driven dyslipidemias. Additionally, strategies aimed at enhancing apolipoprotein A1 and promoting high-density lipoprotein functionality are under investigation, although clinical validation remains ongoing.

Conclusion: This review underscores the evolving landscape of lipid-lowering therapies, with emphasis on agents acting through novel mechanisms beyond statin pathways. Bempedoic acid, by inhibiting ACLY and increasing LDL receptor expression, represents a safe and effective option for reducing LDL-C, especially in statin-intolerant individuals. PCSK9 inhibitors further expand therapeutic options by augmenting LDL receptor recycling and clearance. The integration of these agents into clinical practice may help mitigate residual cardiovascular risk and personalize treatment strategies in dyslipidemia management.

Keywords: Bempedoic acid; Cholesterol; Dyslipidemia; LDL-C; PCSK9 inhibitors; Statins.