Targeting Lipoprotein (a): an Evolving Therapeutic Landscape

Abstract

Robust epidemiologic and genetic studies have solidified the role of lipoprotein (a) [Lp(a)] as an independent and causal risk factor for cardiovascular disease. The increased cardiovascular risk of Lp(a) is mediated through both proatherogenic and prothrombotic/antifibrinolytic mechanisms. Several societies recommend Lp(a) screening for patients with high cardiovascular risk, although no consensus exists on the management of patients with elevated Lp(a). However, numerous pharmacologic approaches are being evaluated that have the potential to reduce Lp(a) and will be the focus of this review. The majority of these interventions have been developed for other lipid-lowering indications, but also lower Lp(a). There are also novel therapies in development that specifically target Lp(a). The efficacy of these therapies varies, and their role in the evolving lipoprotein therapeutic landscape has yet to be determined. Nevertheless, targeted Lp(a) reduction is certainly intriguing and will likely continue to be an active area of investigation in the future.

Lipoprotein (a), an independent cardiovascular risk marker

“…One is mipomersen, an apoB antisense oligonucleotide that inhibits synthesis of apoB. This drug has been approved by FDA for lowering LDL-C, apoB, TC, and non-HDL-C in patients with homozygous familial hypercholesteremia [1, 2, 40]. A meta-analysis investigating the effect of this agent on Lp(a) levels have found a reduction of 26 % in Lp(a) from baseline [1].…”

“…Another development is human monoclonal antibody to Proprotein convertase subtilisin/kexin9 (PCSK9) [1, 2, 40]. PCSK9 is a protein which binds to LDL-receptor (LDL-R).…”

“…The PROFICIO (Program to Reduce LDL and CV Outcomes Following Inhibition of PCSK9 In Different Populations) has shown that administration of Evolocumab, a PCSK9 inhibitor resulted in significant dose-dependent decrease in Lp(a) by up to 29.5 % and LDL-C by 52 % [41]. Alirocumab, another monoclonal antibody, showed similar results as evolocumab in terms of Lp(a) reduction [1, 40]. In a meta-analysis of 20 randomized controlled trials, Li et al demonstrated that treatment with PCSK9 inhibitor resulted in reduction in Lp(a) as well as other lipid parameters such as LDL-C, TC, triglycerides, and apoB.…”

“…In a meta-analysis of 20 randomized controlled trials, Li et al demonstrated that treatment with PCSK9 inhibitor resulted in reduction in Lp(a) as well as other lipid parameters such as LDL-C, TC, triglycerides, and apoB. Even though PCSK9 inhibitors reduce Lp(a), their effect on CVD outcome remains unclear [1, 40]. Also, it is unclear where PCSK9 inhibition fits into current therapeutic guidelines and whether this agent will be used to specifically lower Lp(a) in addition to the robust LDL-C reduction.…”

“…MTP inhibition impair VLDL formation. In phase II clinical trial this agent has been shown to lower Lp(a) by 17 % [40]. There is concern about its hepatotoxicity, thus, it should be prescribed by specifically certified physicians.…”