What is the ultimate test that lowering lipoprotein(a) is beneficial for cardiovascular disease and aortic stenosis?

Abstract

Lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD) and calcific aortic valve stenosis. We review recent studies that highlight Lp(a) in CVD and calcific aortic valve stenosis and propose pathways to clinical registration of Lp(a)-lowering agents. Over the last few years, almost irrefutable evidence has accumulated that Lp(a) is a causal, independent, genetic risk factor for CVD. Most recently, new data have emerged that elevated Lp(a) is causally associated with calcific aortic valve stenosis and the need for aortic valve replacement. Three levels of evidence to support these findings: epidemiological studies, Mendelian randomization studies and genetic association studies. A dedicated Lp(a)-lowering trial has not been performed to date. Emerging Lp(a)-lowering therapies with specific and potent lowering of Lp(a) are in phase II clinical trials and provide a tool to test the hypothesis that lowering Lp(a) plasma levels will lead to clinical benefit. We provide a rationale for the potential clinical use of Lp(a)-lowering therapies in high-risk patients or patients with established CVD whose major risk factor is elevated Lp(a) levels and propose clinical studies and trials to demonstrate that lowering Lp(a) levels will effectively reduce the risk of calcific aortic valve stenosis and CVD.