New insights into the therapeutic options to lower lipoprotein(a)

Background: Elevated levels of lipoprotein(a) [Lp(a)] represent a risk factor for cardiovascular disease including aortic valve stenosis, myocardial infarction and stroke. While the patho-physiological mechanisms linking Lp(a) with atherosclerosis are not fully understood, from genetic studies that lower Lp(a) levels protect from CVD independently of other risk factors including lipids and lipoproteins. Hereby, Lp(a) has been considered an appealing pharmacological target. Results: However, approved lipid lowering therapies such as statins, ezetimibe or PCSK9 inhibitors have a neutral to modest effect on Lp(a) levels, thus prompting the development of new strategies selectively targeting Lp(a). These include antisense oligonucleotides and small interfering RNAs (siRNAs) directed towards apolipoprotein(a) [Apo(a)], which are in advanced phase of clinical development. More recently, additional approaches including inhibitors of Apo(a) and gene editing approaches via CRISPR-Cas9 technology entered early clinical development. Conclusion: If the results from the cardiovascular outcome trials, designed to demonstrate whether the reduction of Lp(a) of more than 80% as observed with pelacarsen, olpasiran or lepodisiran translates into the decrease of cardiovascular mortality and major adverse cardiovascular events, will be positive, lowering Lp(a) will become a new additional target in the management of patients with elevated cardiovascular risk. © 2024 Stichting European Society for Clinical Investigation Journal Foundation.