Considerations for routinely testing for high Lp(a)

Abstract

Purpose of reviewLipoprotein(a) (Lp[a]) is a likely causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve disease, confirmed by Mendelian randomization. With reliable assays, it has been established that Lp(a) is linearly associated with ASCVD. Current low-density lipoprotein cholesterol (LDL-C) lowering therapies do not or minimally lower Lp(a). This review focuses on the clinical importance and therapeutic consequences of Lp(a) measurement.Recent findingsDevelopment of RNA-based Lp(a) lowering therapeutics has positioned Lp(a) as one of the principal residual risk factors to target in the battle against lipid-driven ASCVD risk. Pelacarsen, which is a liver-specific antisense oligonucleotide, has shown Lp(a) reductions up to 90% and its phase 3 trial is currently underway. Olpasiran is a small interfering RNA targeting LPA messenger RNA which is being investigated in phase 2 and has already shown dose-dependent Lp(a) reductions up to 90%.SummaryLp(a) should be measured in every patient at least once to identify patients with very high Lp(a) levels. These patients could benefit from Lp(a) lowering therapies when approved. In the meantime, therapy in high Lp(a) patients should focus on further reducing LDL-C and other ASCVD risk factors.

Potential Novel RNA-Targeting Agents for Effective Lipoprotein(a) Lowering: A Systematic Assessment of the Evidence from Completed and Ongoing Developmental Clinical Trials

“…3). [49][50][51] The mechanism of its action involves the degradation of the mRNA responsible for encoding the production of apo(a), which stops its translation and the assembly of the Lp(a) particle in hepatocytes and decreases the level of Lp(a) in the blood. 23 Like other siRNA therapeutics, olpasiran is basically a double-strand RNA consisting of an antisense and a sense strand.…”

Lipoprotein(a): An important piece of the ASCVD risk factor puzzle across diverse populations

“…Several RNA-targeted Lp(a)-lowering therapies are now entering late-stage clinical development and have demonstrated significant reductions in Lp(a) levels in clinical studies [ 49 ]. Should these novel therapies prove to be well tolerated and effective at reducing ASCVD events, to realize their potential in the clinic fully we must advocate for the widespread adoption of Lp(a) testing to identify patients who may be eligible for pharmacologic treatment in the future [ 51 , 58 , 59 ]. This is especially pertinent given that policy interventions take time to implement and even longer to translate into a measurable change in clinical practice.…”