Lipoprotein(a) [Lp(a)] is a significant, genetically determined contributor to the risk of atherosclerotic cardiovascular disease (ASCVD), which remains the leading cause of mortality worldwide despit Show more
Lipoprotein(a) [Lp(a)] is a significant, genetically determined contributor to the risk of atherosclerotic cardiovascular disease (ASCVD), which remains the leading cause of mortality worldwide despite successes in the management of LDL cholesterol. Lipoprotein(a) possesses increased atherogenicity, contributing to residual cardiovascular risk. Elevated Lp(a) levels affect a substantial proportion of the population, rendering this a potentially high-impact therapeutic target, but currently available lipid-lowering agents and lifestyle interventions have minimal impact on lowering Lp(a), and lipoprotein apheresis is the sole effective-but impractical-method to significantly reduce Lp(a). Recent advances in Lp(a)-targeted therapies, notably nucleic acid-based approaches (e.g. antisense oligonucleotides and small interfering RNAs) and a small molecule inhibitor of Lp(a) synthesis, demonstrated substantial and often durable Lp(a)-lowering effects in Phase II trials. Phase III trials of these agents are now underway to examine the impact of lowering Lp(a) levels on atherosclerotic cardiovascular disease outcomes, and their results may transform the landscape of cardiovascular risk reduction and management for patients with elevated Lp(a). This review summarizes existing lipid-lowering therapies' limited effects on Lp(a), provides an update on the array of emerging therapeutics and their safety and efficacy, and discusses ongoing Phase III trials as well as other potential benefits of Lp(a)-lowering, such as slowing progression of calcific aortic valve stenosis. Show less
Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with Show more
Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction. Show less